Ocular Pressure & Retina Defense [Discontinued] by Whitaker Nutrition

POSSIBLY INEFFECTIVE

• Night vision. Most research suggests that oral bilberry does not improve night vision in healthy individuals. Details: There is contradictory evidence about the effectiveness of bilberry for improving night vision; however, much of the research is of poor quality. In general, the most rigorous research shows that bilberry is not effective for improving night vision in healthy individuals (8139,9739,14280,35446). Whether bilberry can improve night vision in patients with night blindness is unclear.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of elderly Norwegian males with subjective cognitive impairment shows that drinking 330 mL of bilberry and red grape juice twice daily for 9 weeks does not improve measures of memory or motor skills when compared with placebo (110641).
• Age-related macular degeneration (AMD). Although there has been interest in using oral bilberry for AMD, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Asthenopia (eye strain). Small clinical studies suggest that oral bilberry fruit extract may improve objective measures of asthenopia, but it is unclear if oral bilberry improves subjective symptoms of asthenopia. Details: Two small clinical studies in adults who report general eye strain or those who look at computer or other display screens at work for long periods of time show that taking bilberry-derived anthocyanins 43.2 mg daily for 6 weeks or bilberry extract 240 mg daily for 12 weeks improves objective measures of eye strain after staring at computer screens when compared with placebo (103190,104195). However, bilberry extract did not improve subjective measures of eye strain in the study that evaluated these outcomes (104195). This study may have been underpowered to detect significant differences between groups. Bilberry has also been evaluated in combination with other ingredients for improving eye strain. A small clinical trial in patients with eye strain shows that a combination of fish oil, lutein, and bilberry extract containing bilberry anthocyanidins 59 mg, taken daily for 4 weeks, reduces dry eye, lower back pain, shoulder stiffness, and stuffy head when compared with placebo (35470). It is unclear if these effects are due to bilberry, other ingredients, or the combination.
• Atherosclerosis. Although there has been interest in using oral bilberry for atherosclerosis, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Cataracts. Although there has been interest in using oral bilberry for cataracts, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Chronic venous insufficiency (CVI). It is unclear if oral bilberry is beneficial in patients with CVI. Details: One small clinical study in patients with CVI shows that taking bilberry extract containing anthocyanins 173 mg daily for 30 days reduces symptoms of CVI when compared with placebo (35510).
• Diabetes. It is unclear if oral bilberry is beneficial in patients with diabetes. Details: One small clinical trial in patients with type 2 diabetes shows that taking a specific extract of bilberry fruit (Mirtoselect, Indena S.p.A) 470 mg once, prior to taking an oral glucose tolerance test, lowers plasma glucose levels when compared with placebo (91507). However, a small crossover trial in Chinese patients with type 2 diabetes shows that taking bilberry fruit extract 700 mg twice daily for 4 weeks does not improve glycated hemoglobin (HbA1c), body weight, blood pressure, or lipid levels when compared with placebo (104194). The validity of the HbA1c-related findings is limited due to the short study duration.
• Diabetic retinopathy. It is unclear if oral bilberry is beneficial in patients with diabetic retinopathy. Details: One small clinical trial in adults with diabetic and hypertensive retinopathy shows that taking bilberry fruit extract 160 mg daily for 6 months, in addition to standard management, improves edema and measures of retinal circulatory health when compared with standard management alone. Bilberry in the form of a generic, commercially available product appears to produce less dramatic improvements than a branded formulation (Mirtoselect, Indena S.p.A.) containing matching anthocyanin content. This specific product also reduced flow velocity in those with high-flow, diabetic retinopathy when compared with either the generic bilberry extract or standard management alone (97032).
• Dry eye. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with severe dry eye symptoms suggests that taking bilberry extract 600 mg and docosahexaenoic fish oil 240 mg once daily for 3 months may modestly improve measures of tear quality and patient-reported scores for dry eye symptoms when compared with control (112415). However, the validity of these results is limited by the lack of a statistical comparison between groups. Additionally, it is unclear if these effects are due to bilberry, fish oil, or the combination.
• Dysmenorrhea. It is unclear if oral bilberry is beneficial in patients with dysmenorrhea. Details: One small clinical study in patients with dysmenorrhea shows that a specific bilberry product (Tegens) containing bilberry anthocyanoside 160 mg, taken twice daily beginning 3 days prior to menses and continuing for 8 days, reduces pelvic pain, lumbosacral pain, breast pain, nausea, vomiting, and headache when compared with placebo (35512).
• Exercise-induced muscle soreness. It is unclear if oral bilberry is beneficial for reducing exercise-induced muscle soreness. Details: A small clinical study in trained athletes shows that drinking 200 mL of bilberry juice, containing about 744 mg phenols and 80 mg anthocyanins, twice daily for 5 days prior to running a half-marathon modestly worsens muscle soreness immediately after the run when compared with placebo. There was no longer a difference in muscle soreness between groups within 1-2 days after the run (99540).
• Glaucoma. Small clinical studies suggest that oral bilberry fruit extract, when taken with maritime pine extract, may lower intraocular pressure in patients with glaucoma. It is unclear if oral bilberry alone is beneficial in patients with glaucoma. Details: One small, uncontrolled clinical trial in Japanese patients with open-angle glaucoma shows that taking a specific product (Sante Glagenox, Saten Pharmaceutical Co. Ltd.) containing bilberry fruit extract 90 mg and maritime pine extract 40 mg daily for 4 weeks reduces intraocular pressure by 8.7% when compared to baseline (104192). Another small clinical study in patients with high intraocular pressure shows that taking a specific product (Mirtogenol) containing bilberry fruit extract (Mirtoselect, Indena S.p.A.) 80 mg and maritime pine extract (Pycnogenol, Horphag Research) 40 mg twice daily for 6 months lowers intraocular pressure and improves intraocular blood flow when compared with no treatment (35456). It is unclear if these findings are due to bilberry, maritime pine, or the combination. A retrospective chart review of patients with normal tension glaucoma has found that taking bilberry anthocyanin 60 mg twice daily for at least 12 months is associated with improvements in visual function when compared to pretreatment (35472).
• Hemorrhoids. Although there has been interest in using oral bilberry for hemorrhoids, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Hyperlipidemia. It is unclear if oral bilberry is beneficial in patients with hyperlipidemia. Details: A small clinical study in adults with hyperlipidemia shows that taking bilberry-derived anthocyanins 320 mg daily for 4 weeks does not improve total cholesterol, low-density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, or triglyceride levels. Further, no improvements in other biomarkers of cardiovascular disease were reported (110640). The validity of this study is limited by its short duration.
• Hypertension. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in adults with hypertension shows that consuming 500 mL of a juice containing bilberry, red grape, and chokeberry, with or without black currant (MANA Blue, TINE SA), daily for 12 weeks does not improve blood pressure when compared with placebo (92371).
• Hypertensive retinopathy. It is unclear if oral bilberry is beneficial in patients with hypertensive retinopathy. Details: One small clinical trial in adults with diabetic and hypertensive retinopathy shows that taking bilberry fruit extract 160 mg daily for 6 months, in addition to standard management, improves edema and measures of retinal circulatory health when compared with standard management alone. Bilberry in the form of a generic, commercially available product appears to produce less dramatic improvements than a branded formulation (Mirtoselect, Indena S.p.A.) containing matching anthocyanin content. This specific product also increased flow velocity for those with ischemic, hypertensive retinopathy when compared with either the generic bilberry extract or standard management alone (97032).
• Impaired glucose tolerance (prediabetes). Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with impaired glucose tolerance and two markers of metabolic syndrome shows that consuming a diet high in whole grain products, fatty fish, and bilberries three times daily for 12 weeks reduces levels of plasma glucose when compared to baseline (35468). However, it is unclear if these findings are due to bilberry, another component of the diet, or the combination.
• Irritable bowel syndrome (IBS). Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in adults with IBS shows that consuming a formula containing powdered bilberry fruit, aerial agrimony parts, cinnamon quills, and slippery elm bark modestly improves bowel movement frequency and reduces symptoms such as abdominal pain, bloating, flatulence, and straining when compared to baseline (35462). It is unclear if these findings are due to bilberry, other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral bilberry is beneficial in patients with metabolic syndrome. Details: One small clinical study in patients with metabolic syndrome shows that consuming a diet containing 400 grams of fresh bilberries daily does not affect body weight, glucose metabolism, or lipid metabolism when compared with a control diet (35473).
• Myopia. It is unclear if oral bilberry is beneficial in patients with myopia. Details: One small clinical trial in adults with myopia shows that a specific fermented bilberry fruit extract (Fermented Blueberry, Ajinomoto, Co., Inc.) 200 mg, taken twice daily for 4 weeks, improves night vision as well as the eye's ability to adjust focus when compared with placebo. The amplitude of accommodation was also significantly increased from 4.62 to 5.33 (91505).
• Obesity. It is unclear if oral bilberry is beneficial in patients with obesity. Details: One small clinical study in obese and overweight females shows that consuming 100 grams of frozen, whole bilberries daily for 33-35 days decreases weight and waist circumference when compared to baseline (35463). The validity of these findings is limited by the lack of a comparator group.
• Osteoarthritis. Although there has been interest in using oral bilberry for osteoarthritis, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Ulcerative colitis. It is unclear if oral bilberry is beneficial in patients with ulcerative colitis. Details: One small, open-label clinical study in adults with mild-to-moderate ulcerative colitis shows that consuming sieved bilberries and concentrated bilberry juice (Symrise GmbH & Co) 160 grams daily for 6 weeks induces remission in 46% of patients. Furthermore, 91% of patients achieved remission at the end of treatment, and 72% of patients achieved remission at the end of the study (91506). The validity of these findings is limited by the lack of a comparator group.
• Urinary tract infections (UTIs). Although there has been interest in using oral bilberry for UTIs, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Varicose veins. Although there has been interest in using oral bilberry for varicose veins, there is insufficient reliable information about the clinical effects of bilberry for this purpose. More evidence is needed to rate bilberry for these uses.

(Read more about BILBERRY)

POSSIBLY EFFECTIVE

• Asthma. Oral maritime pine bark extract, taken as an adjunct to conventional asthma medications, may improve symptoms and reduce rescue inhaler use in patients with asthma. Details: Three small clinical studies in children and adults with asthma of varying severity show that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 1 mg/lb body weight or 100 mg daily in addition to conventional asthma medications increases peak expiratory flow, decreases asthma symptoms, and decreases the need for rescue medications when compared with conventional therapy alone (13120,50863,50926). Maritime pine bark extract has not been studied as monotherapy for asthma and should not be used in place of conventional medicine for this purpose.
• Chronic venous insufficiency (CVI). Oral maritime pine bark extract may improve leg pain and heaviness and reduce edema in patients with CVI. Details: Several clinical studies in patients with CVI show that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) reduces edema, the rate of ankle swelling, and symptoms of leg pain and heaviness when used for 3-12 weeks. The most commonly used dose is 100-120 mg three times daily (2451,2462,2493,7693,50892). However, lower doses of 50 mg three times daily (16906,50892,50900,50915) or 45-100 mg once daily also seem to be effective (2435,97401). When compared with the use of below-knee compression stockings worn throughout the day, maritime pine bark reduces induration and the rate of ankle swelling when compared to baseline in patients with CVI. While both treatments reduce venous edema and pain when compared with baseline, a more pronounced reduction is seen in patients taking the maritime pine bark extract (97401). Other clinical research in adults who have had CVI for more than 3 years shows that taking the same extract, 50 mg three times daily for 8 weeks, in addition to wearing compression stockings, improves microcirculation and subjective symptom scores when compared with compression stockings alone (103616). However, compliance with the use of compression stockings in this study was poor.
• Osteoarthritis. Small clinical studies suggest that oral maritime pine bark extract may modestly improve symptoms and reduce the need for analgesics in patients with knee osteoarthritis. Details: Two small clinical studies in patients with knee osteoarthritis shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 100-150 mg daily for 3 months reduces overall osteoarthritis symptoms, pain, and the use of anti-inflammatory medication when compared with placebo (50903,50905). Topical maritime pine bark has also been evaluated. Observational research in patients with knee osteoarthritis found that applying standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 220 mg, as two patches daily, for three weeks is associated with reduced pain and reduced need for rescue analgesics when compared with control (100356).

POSSIBLY INEFFECTIVE

• Hyperlipidemia. Oral maritime pine bark extract may not improve lipid levels in patients with hyperlipidemia. Details: Although individual clinical trials have shown mixed results (7693,91965,97408), a meta-analysis of 4 small clinical trials in patients with hyperlipidemia shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 100-150 mg daily for 4-24 weeks does not reduce total cholesterol, low-density lipoprotein (LDL) cholesterol, or triglyceride levels when compared with a control (100357).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral maritime pine bark extract is beneficial in elderly patients with age-related cognitive decline. Details: One observational registry study in healthy elderly patients ages 55-70 years has found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 100 mg daily for 12 months is associated with improved cognitive function, mental performance, and attention when compared with matched controls (97405). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study. Also, a small clinical study in healthy elderly patients 60-85 years of age shows that taking the same extract, 150 mg daily for 3 months, improves spatial working memory, but not numeric working memory, episodic memory, attention, or psychomotor performance, when compared with placebo (50906).
• Aging skin. Although there has been interest in using oral and topical maritime pine for aging skin, there is insufficient reliable information about the clinical effects of maritime pine for this purpose.
• Allergic rhinitis (hay fever). It is unclear if oral maritime pine bark extract is beneficial in people with allergic rhinitis. Details: A small clinical study in patients with birch allergies shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg twice daily, starting at least 5 weeks before allergy season, decreases nasal symptoms associated with birch allergies when compared with placebo (17300).
• Androgenic alopecia. It is unclear if oral maritime pine bark is beneficial for androgenic alopecia. Details: A small clinical study in postmenopausal patients conducted in China shows that taking maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 6 months improves hair density when compared to baseline (112713). However, the interpretation of these findings is limited by the lack of a statistical comparison to the placebo group.
• Antidepressant-induced sexual dysfunction. It is unclear if oral maritime pine bark is beneficial for improving sexual function in adults taking escitalopram. Details: A small, open-label clinical study shows that taking standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg daily for 4 months with escitalopram 10-20 mg daily seems to improve sexual dysfunction when compared with escitalopram alone (100361).
• Atherosclerosis. Oral maritime pine bark extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A non-randomized clinical trial in adults with atherosclerosis shows that taking a specific maritime pine bark product (Pycnogenol, Horphag Research) 150 mg and gotu kola 225 mg, in two divided doses daily for 3 months, reduces plaque height and length and increases plaque echogenicity and stability when compared to control (97030). However, these benefits may be at least partially due to gotu kola. Another non-randomized clinical study in adults with atherosclerotic plaques and no other cardiovascular risk factors shows that taking Pycnogenol 100 mg and gotu kola extract 100 mg daily for up to 4 years reduces plaque progression and increases plaque echogenicity to a greater extent than Pycnogenol alone or no treatment at all. Taking Pycnogenol with gotu kola is also associated with a reduced rate of clinical vascular events, including angina, myocardial infarction, minor transient ischemic attacks (TIAs), and minor strokes, when compared with taking Pycnogenol alone or receiving no treatment at all (97029).
• Athletic performance. It is unclear if oral maritime pine bark extract is beneficial for improving exercise capacity in recreationally trained adults; the available evidence is conflicting. Details: One small clinical study shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 200 mg orally daily for 30 days improves exercise capacity during a treadmill test in recreational athletes aged 20-35 years (2554). Additionally, an observational registry study found that taking this same maritime pine bark extract 100 mg orally daily for 8 weeks along with training improves performance in the Army Physical Fitness Test, including reducing two-mile treadmill time by about 45-60 seconds and increasing the number of push-ups and sit-ups by about 5-7 when compared to control training alone. Taking this maritime pine bark extract during training also appears to improve total triathlon time by about 6 minutes when compared with training alone (91966). However, the validity of this finding is limited by the unblinded, non-randomized nature of the study. Additionally, a small study in college-age males who exercise regularly shows that taking the same maritime pine bark extract 800 mg daily, starting 14 days prior to a cycle ergometer test and continuing for 2 days after, does not improve maximum oxygen consumption or power generated in the test when compared with placebo (103617). Maritime pine extract has also been studied in combination with other ingredients. A small clinical study in non-professional athletes shows that taking a combination product (PycnoRacer, Kobayashi Pharmaceutical Company) containing maritime pine extract 15 mg, L-leucine 0.6 grams, L-arginine 0.3 grams, L-isoleucine 0.3 grams, and L-valine 0.3 grams four times daily for 3 weeks during training improves running distance by about 19%, compared with 9% in athletes drinking water plus Gatorade. Maritime pine park also improved maximal oxygen consumption and reduced subjective scores of muscle pain and cramps when compared with water and Gatorade (103613). It is unclear if these benefits are due to maritime pine, other ingredients, or the combination.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral maritime pine bark extract is beneficial in children or adults with ADHD. Details: A small clinical study in adults with ADHD shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) does not seem to improve ADHD symptoms when compared with placebo (9984). However, a small clinical study in children with ADHD shows that taking this standardized maritime pine bark extract 1 mg/kg daily for one month appears to improve attention and hyperactivity scores when compared with placebo (50891).
• Behcet syndrome. It is unclear if oral maritime pine bark extract is beneficial in patients with Behcet syndrome. Details: A small clinical study in patients with Behcet syndrome shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 3 weeks reduces skin ulcer size and improves self-reported symptoms of burning and pain when compared to baseline (100358). The validity of these findings is limited by the lack of a comparator group.
• Benign prostatic hyperplasia (BPH). It is unclear if oral maritime pine bark extract is beneficial in patients with BPH. Details: A small observational registry study in patients with BPH found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 8 weeks is associated with modest improvement of symptoms such as bladder emptying, urgency, flow, straining, and nocturia (100359). This study was limited by small size, reporting inaccuracies, and its unblinded, non-randomized design.
• Cognitive function. Small clinical studies suggest that oral maritime pine bark extract might improve cognitive function in healthy adults. Details: A small observational registry study in healthy adults aged 30-55 years found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 12 weeks is associated with slightly improved memory and cognition when compared with matched controls (97410). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study. A small clinical study in healthy college students also shows that taking the same extract 100 mg daily for 2 months seems to reduce failed tests by 4.5% and improve average test scores by about 8% when compared with control (50928).
• Cognitive impairment. It is unclear if oral maritime pine bark extract improves cognitive function in patients with mild cognitive impairment. Details: An observational registry study in adults with mild cognitive impairment found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 8 weeks improves global cognitive function when compared to no supplementation. All patients in this study also received standard management of mild cognitive impairment, which included lifestyle modifications such as improved sleep, physical exercise, reduced sugar and salt intake, lowering cardiovascular risk factors, and avoiding use of stimulants or depressants (97406). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Common cold. It is unclear if oral maritime pine bark extract is beneficial in the treatment of the common cold. Details: An observational registry study in otherwise healthy adults with a cold found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg twice daily, along with best management for colds, is associated with about one less day of a perceived cold when compared to "best management" alone. This standardized maritime pine bark extract is also linked to reduced use of over-the-counter products to manage symptoms in cases of colds lasting longer than 4 days (91962). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Dental plaque. It is unclear if chewing gum containing maritime pine bark extract can reduce dental plaque. Details: A small clinical study shows that chewing a minimum of six pieces of gum containing a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 5 mg daily for 14 days reduces gingival bleeding by 55% and prevents an increase in gingival plaque when compared with a control sugar-free gum (50857).
• Diabetes. Small clinical studies suggest that oral maritime pine bark extract may modestly improve glycemic control in patients with type 2 diabetes. Details: Three small clinical studies in patients with type 2 diabetes show that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50-200 mg daily for 3-12 weeks modestly decreases blood glucose and glycated hemoglobin (HbA1C) levels when compared with placebo (15521,15522,50908). Another small clinical trial in patients with type 2 diabetes and microalbuminuria shows that taking a different standardized maritime pine bark extract (Oligopin, DRT Group) 100 mg daily for 8 weeks reduces HbA1c by around 1%, but does not reduce fasting blood glucose, when compared with placebo (105781).
• Diabetic foot ulcers. It is unclear if oral or topical maritime pine bark extract is beneficial for diabetic foot ulcers. Details: A small clinical study in patients with diabetic foot ulcers shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily orally as well as applying the extract topically 100 mg daily heals ulcers in 89% of subjects compared with 61% of control subjects. Using oral or topical maritime pine bark extract alone seems to result in complete ulcer healing in about 85% of subjects (50896).
• Diabetic microangiopathy. It is unclear if oral maritime pine bark extract is beneficial in patients with diabetic microangiopathy. Details: A small, unblinded clinical study in patients with diabetic microangiopathy, symptoms of neuropathy, and edema in the absence of severe cardiovascular disease shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg three times daily for 4 weeks improves microcirculation (measured by laser Doppler flowmetry) and symptoms when compared with no treatment (15523).
• Diabetic retinopathy. It is unclear if oral maritime pine bark extract is beneficial in patients with diabetic retinopathy. Details: A small, unblinded clinical study in patients with retinopathy due to various causes, including diabetes, atherosclerosis, or central venous thrombosis, shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg three times daily for 2 months may slow or prevent further deterioration of retinal function when compared with no treatment (2536).
• Dry mouth. It is unclear if oral maritime pine bark extract is beneficial in patients with dry mouth. Details: Two small observational studies in otherwise healthy adults or patients with diabetes suggest that adding a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) for 2 weeks along with standard saliva supplements is associated with improvement in patient-reported mouth dryness, salivary flow, and the number of small mucosal breaks when compared with saliva supplements alone. One study dosed maritime pine bark extract 150 mg orally daily and the other used a spray formulation dosed 10 mg six times daily (103612,112714). However, the validity of these findings is limited by the unblinded, non-randomized nature of the studies.
• Dysmenorrhea. It is unclear if oral maritime pine bark extract is beneficial in patients with dysmenorrhea. Details: Two small clinical studies in patients with dysmenorrhea show that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 30-60 daily for up to 3 menstrual cycles reduces pain when compared to baseline (15424,50904). The validity of this finding is limited by the lack of a comparator group.
• Erectile dysfunction (ED). Small clinical studies suggest that oral maritime pine bark extract, taken alone or in combination with L-arginine, may modestly improve sexual function in patients with ED. Details: Several small clinical studies in adults with ED show that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) at a dose of 120 mg daily for 3 months, either alone (12012) or in combination with L-arginine (10416,32149,50924), might improve sexual function when compared with placebo or baseline measurements. It seems to take up to 3 months of treatment for significant improvement. Similarly, a meta-analysis of 2 small clinical studies in males with mild to moderate ED shows that taking maritime pine 80 mg with L- arginine daily for 1-6 months improves International Index of Erectile Dysfunction scores by 9 points when compared with control (112715). It is unclear if this effect is from maritime pine, L-arginine, or the combination.
• Exercise-induced muscle soreness. Oral maritime pine bark extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in non-professional athletes shows that taking a combination product (PycnoRacer, Kobayashi Pharmaceutical Company) containing maritime pine extract 15 mg, L-leucine 0.6 grams, L-arginine 0.3 grams, L-isoleucine 0.3 grams, and L-valine 0.3 grams four times daily for 3 weeks during training improves subjective scores for muscle pain and cramps when compared with water plus Gatorade (103613). It is unclear if these benefits are due to maritime pine, other ingredients, or the combination.
• Glaucoma. Oral maritime pine has only been evaluated in combination with other ingredients; its effects when used alone is unclear. Details: One small, unblinded clinical trial in Japanese patients with open-angle glaucoma shows that taking a specific product (Sante Glagenox, Saten Pharmaceutical Co. Ltd.) containing maritime pine extract 40 mg and bilberry fruit extract 90 mg daily for 4 weeks reduces intraocular pressure by 8.7% when compared to baseline (104192). The validity of this finding is limited by the lack of a comparator group.
• Heart failure. Oral maritime pine bark extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small observational study in patients with mild to moderate heart failure has found that taking a specific combination product (PycnoQ10, Natural Health Science Inc.) containing a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) and coenzyme Q10 for 12 weeks is associated with improved exercise capacity and heart function (44178). It is unclear if these findings are due to maritime pine, coenzyme Q10, or the combination.
• Hemorrhoids. It is unclear if oral or topical maritime pine bark extract is beneficial in patients with hemorrhoids. Details: A small clinical study in patients with acute hemorrhoidal episodes shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150-300 mg daily orally, alone or in combination with a cream containing 0.5% standardized maritime pine bark extract (Pycnogenol, Horphag Research) for 7 days, improves both quality of life and hemorrhoidal symptoms when compared with placebo tablets/cream (50912). Additionally, an observational registry study in postpartum adults with internal or external hemorrhoids found that taking this same extract of maritime pine bark 150 mg daily for 6 months, in conjunction with standard hemorrhoid care, is associated with improved symptoms, including thrombosis, pain, swelling, and bleeding, when compared to standard care alone (97416). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Hypertension. It is unclear if oral maritime pine bark reduces blood pressure; the available research is conflicting. Details: A very small clinical study in patients with mild hypertension (systolic 140-159 mm Hg; diastolic 90-99 mm Hg) shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 200 mg daily for 8 weeks may modestly reduce systolic, but not diastolic, blood pressure when compared with placebo (10214). Another very small study in hypertensive patients treated with ramipril, taking this same standardized maritime pine bark extract 50 mg three times daily for 6 months, appears to further reduce diastolic, but not systolic, blood pressure (50913). Conflicting results have been reported with other maritime pine products. A small clinical study in adults with untreated, mild hypertension shows that taking a different standardized extract of maritime pine (Oligopin, DRT Group), 75 mg twice daily for 5 weeks, does not lower systolic or diastolic blood pressure when compared with placebo (97407). Also, a small clinical study in obese patients with prehypertension or hypertension shows that taking a different maritime pine bark extract (Toyo-FVG, Toyo Bio-Pharma) 200 mg daily for 12 weeks does not lower systolic or diastolic blood pressure when compared with placebo (50919). Results of meta-analyses are also contradictory. An analysis of 7 clinical trials using maritime pine bark extract 90-200 mg daily for 2-24 weeks shows no significant effect overall on systolic or diastolic blood pressure, mean arterial pressure, or pulse pressure (103609). However, an analysis of 12 trials using doses of 60-200 mg daily for 4-24 weeks shows a mean reduction of about 3 mmHg in systolic blood pressure, and about 2 mmHg in diastolic blood pressure. There was high heterogeneity between the studies, and the effect on diastolic blood pressure was only seen with a treatment duration of at least 12 weeks (103610).
• Idiopathic interstitial pneumonia. Oral maritime pine bark extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small observational registry study in males less than 65 years old with idiopathic interstitial pneumonia has found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg three times daily in combination with gotu kola (Centellicum; Horphag Research) 225 mg three times daily for 8 months is associated with a modest improvement in Karnofsky Performance Scale scores and a reduction in fatigue when compared with pirfenidone (108862). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Irritable bowel syndrome (IBS). It is unclear if oral maritime pine bark extract is beneficial in patients with IBS. Details: An observational registry study in adults with idiopathic IBS found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 4 weeks, in conjunction with standard treatment, is associated with reduced abdominal pain, cramps, and the use of medical care and rescue medications when compared to standard treatment alone. In both groups, standard treatment included specific nutritional recommendations and Buscopan Compositum, hyoscine-N-butylbromide, or acetaminophen for pain relief (97402). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Jet lag. It is unclear if oral maritime pine bark extract can prevent or treat jet leg. Details: An observational registry study found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for up to 10 days, starting 3 days before a plane flight, is associated with reduced signs and symptoms of jet lag when compared to control (97437). Additionally, a small clinical study shows that taking this extract 50 mg three times daily for 7 days, starting 2 days before a plane flight, reduces jet lag symptoms and the average duration of symptoms by a little over 1 day when compared with placebo (97412).
• Leg cramps. It is unclear if oral maritime pine bark extract is beneficial for leg cramps. Details: A small clinical study in patients experiencing at least 4 episodes of leg cramps per week associated with athletic activity, venous insufficiency, or an unknown cause shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 200 mg daily for 4 weeks may decrease the incidence of leg cramps when compared to baseline (15524). The validity of this finding is limited by the lack of a comparator group.
• Male infertility. Although there has been interest in using oral maritime pine for male infertility, there is insufficient reliable information about the clinical effects of maritime pine for this purpose.
• Melasma. It is unclear if oral maritime pine bark extract is beneficial for melasma. Details: A small clinical study in females with melasma shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 75 mg twice daily for 60 days, along with topical application of sunscreen during the day and a triple cream containing hydroquinone, tretinoin, and fluocinolone at night, improves scores related to melasma severity and aesthetics, but not quality of life, when compared with placebo plus sunscreen and triple cream (105782).
• Meniere disease. It is unclear if oral maritime pine bark extract is beneficial in patients with Meniere disease. Details: Observational registry research in patients with Meniere disease found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily along with standard treatment is associated with a greater reduction in the severity of tinnitus and the number of work-days lost when compared with standard treatment alone. After 6 months of treatment, about 87% of patients taking maritime pine bark were asymptomatic, compared to about 35% of patients receiving standard treatment alone (97413). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Menopausal symptoms. Small clinical studies suggest that oral maritime pine bark extract might improve some menopausal symptoms. Details: Several small clinical studies in patients with menopausal symptoms shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 60-200 mg daily for 2-6 months modestly reduces perimenopausal symptoms, including tiredness, headache, depression and anxiety, sleep disturbances, vaginal dryness, hot flashes, and loss of memory, when compared with placebo or control (14899,50927,50945).
• Metabolic syndrome. It is unclear if oral maritime pine bark extract is beneficial in patients with metabolic syndrome. Details: A small clinical study in patients with metabolic syndrome shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg three times daily for 6 months lowers triglyceride levels by 46 mg/dL, increases high-density lipoprotein (HDL) cholesterol levels by about 10 mg/dL, reduces fasting plasma glucose by 18 mg/dL, and lowers systolic and diastolic blood pressure by 7 mmHg and 5 mmHg, respectively, when compared to baseline. The validity of these findings is limited by the lack of statistical comparison to a control group. Taking the maritime pine bark extract was also associated with a reduction in the percentage of patients presenting with five risk factors of metabolic syndrome (91960).
• Oral mucositis. It is unclear if topical maritime pine bark extract is beneficial in children with chemotherapy-related oral mucositis. Details: A small clinical study in children 6-15 years of age with chemotherapy-related oral mucositis shows that application of a solution containing a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 1 mg/kg in three divided doses daily for one week promotes complete healing in 58% of patients and improved healing in 38% of patients. This improvement was significantly greater than treatment with glycerine solution and similar to treatment with vitamin E solution (91964).
• Osteopenia. It is unclear if maritime pine bark extract is beneficial in patients with osteopenia. Details: A small clinical study in postmenopausal adults with osteopenia shows that taking a standardized extract of maritime pine bark (Oligopin, DRT Group) 150 mg daily for 12 weeks improves markers of bone turnover when compared with placebo (105783). It is unknown if maritime pine bark extract improves bone mineral density or reduces the risk of fractures in patients with osteopenia.
• Parkinson disease. It is unclear if oral maritime pine bark extract is beneficial in patients with Parkinson disease. Details: Two small observational studies in adults with mild to moderate Parkinson disease suggest that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 4 or 8 weeks in conjunction with carbidopa/levodopa therapy is associated with a reduction in scores for tremor, bradykinesia, and rigidity when compared with carbidopa/levodopa therapy alone. Maritime pine is also associated with an increase in the Karnofsky Performance Status Scale score from approximately 75 (cares for self, unable to carry on normal activity or do active work) to approximately 85 (normal activity with effort, some signs or symptoms of disease), compared with little to no change from a score of around 75 in the control group (103614,112716).
• Pregnancy-related pain. It is unclear if oral maritime pine bark extract is beneficial for reducing pain during the third trimester of pregnancy. Details: A small clinical study in patients in the third trimester of pregnancy shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 30 mg daily modestly reduces lower back pain, hip joint pain, pelvic pain, and pain due to varicose veins or calf cramps when compared with a control group (15423).
• Psoriasis. It is unclear if oral maritime pine bark extract is beneficial in patients with psoriasis. Details: An observational registry study in adults with moderate to severe plaque psoriasis found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 12 weeks along with standard treatment is associated with improved quality of life, increased water and moisture content of the skin, reduced plaque severity and total affected body area, and reduced use of corticosteroids when compared with standard treatment alone (97417). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Raynaud syndrome. It is unclear if oral maritime pine bark extract is beneficial in patients with Raynaud syndrome. Details: A small clinical study in females with mild, primary Raynaud syndrome shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg twice daily for 4 weeks decreases coldness, burning pain, paresthesias, skin color changes, and low temperature areas of the hands when compared with lifestyle changes alone. The lowest finger temperature increased by 30% in those taking this product, compared with 13% in those implementing lifestyle changes alone (103615).
• Restless legs syndrome (RLS). It is unclear if oral maritime pine is beneficial for RLS. Details: A small observational study in adults with RLS suggests that taking maritime pine bark extract (Pycnogenol, Horphag Research) 150 mg daily along with standard management (i.e., regular sleep, exercise, vitamin C, B vitamins, proper footwear, and instruction on diet and posture) improves self-reported symptoms associated with RLS when compared to baseline. Maritime pine bark may also be associated with less analgesic use compared with standard management alone (112717). However, the interpretation of these findings, other than analgesic use, is limited by lack of a statistical comparison to the other study group.
• Sarcopenia. It is unclear if oral maritime pine bark extract is beneficial in patients with sarcopenia. Details: Observational registry research in adults over 70 years of age with signs of muscle loss has found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily along with strength training for 2 months improves hand grip strength, walking distance, total weight lifted, number of steps climbed, and general fitness scores when compared with strength training alone (97404). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Sexual dysfunction. Oral maritime pine bark extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with sexual dysfunction shows that taking a specific combination tablet (Lady Prelox, Horphag Research) containing a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 20 mg, L-arginine 200 mg, L-citrulline 200 mg, and a standardized rose hip extract (Rosvita) orally 50 mg daily for 8 weeks, in combination with a management program consisting of lifestyle, diet, exercise, and stress control changes, improves overall sexual function when compared with the management program alone (91963). Taking the same product in a dose of 2 tablets twice daily for 8 weeks, in addition to the lifestyle management program, improves vaginal dryness in pre- and post-menopausal patients when compared with lifestyle management alone (103611). The effect of maritime pine alone on sexual dysfunction is unclear.
• Sjogren syndrome. It is unclear if oral maritime pine bark extract is beneficial in patients with Sjogren syndrome. Details: A very small observational study in patients with Sjogren syndrome found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily in addition to standard therapy is associated with a reduction in dry eye, dry mouth, and the need for corticosteroids when compared with standard therapy alone (100360).
• Systemic lupus erythematosus (SLE). It is unclear if oral maritime pine bark extract is beneficial in patients with SLE. Details: A very small clinical study in adults with SLE shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 120 mg daily for 30 days, followed by 60 mg daily for 30 days, modestly reduces symptoms of SLE in some patients when compared with control (50851).
• Traumatic brain injury (TBI). It is unclear if oral maritime pine bark extract is beneficial in patients with TBI. Details: A clinical study in patients admitted to the intensive care unit with TBI shows that administering a standardized maritime pine bark extract (Oligopin, DRT Group) 50 mg three times daily with enteral nutrition for 10 days improves scores on the sequential organ failure assessment (SOFA) and APACHE II [Acute Physiology and Chronic Health Evaluation II], as well as nutritional status, when compared with placebo. At day 28, survival rate was 86% in the treatment group, compared to 71% in the placebo group; however, this difference was not statistically significant (108861).
• Urinary tract infections (UTIs). It is unclear if oral maritime pine bark extract is beneficial in patients with recurrent UTIs or interstitial cystitis. Details: An observational registry study in adults aged 30-40 years with a recent history of recurrent UTIs has found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 2 months is associated with a normal urinalysis in 92% of patients, compared with 68% of those who received no supplementation (108860). Another observational registry study in patients with recurrent UTIs or interstitial cystitis has found that taking this same dose for 2 months is associated with a normal urinalysis in 100% of patients, compared with 35% of patients who took oral cranberry extract 400 mg daily and 36% of those who received no treatment (108859). However, the validity of these findings is limited by the unblinded, non-randomized nature of these studies.
• Varicose veins. It is unclear if oral maritime pine bark extract is beneficial in patients with varicose veins. Details: Observational registry research in postpartum adults has found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg daily for 6 months, in addition to using below-knee compression stockings, is associated with reduced edema, leg cramps, total number of varicose veins, and number of visible spider vein clusters when compared with compression stockings alone (97403). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Venous thromboembolism (VTE). While some conflicting evidence exists, low-quality clinical research suggests that oral maritime pine bark extract might prevent superficial thrombosis during flights and reduce the incidence of post-thrombotic syndrome (PTS) in patients with a history of deep vein thrombosis (DVT). Details: Observational registry research has found that a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 10 days is not associated with reduced occurrence of DVT, a type of VTE, when compared with compression stockings or control (97437). However, an older clinical study in patients at moderate or high risk for thrombotic events shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 200 mg 2-3 hours before a flight seems to reduce superficial thrombosis, but not DVT risk, when compared with placebo (50874). Some observational research also has also found that taking standardized maritime pine bark extract (Pycnogenol, Horphag Research) is associated with reduced post-thrombotic syndrome (PTS) and recurrent DVT (100355). Also, some clinical research shows that taking standardized extract of maritime pine bark (Pycnogenol, Horphag Research) daily for one year, while wearing or not wearing compression stockings, reduces the incidence of PTS in patients with a single prior episode of DVT (50925). Maritime bark has also been studied in combination with other natural products. There is some evidence that taking a specific combination product (Flite Tabs, Aidan Products) before a flight and then again 6 hours later might decrease the risk of DVT during long-haul plane flights in high-risk patients. The product combines a blend of 150 mg of standardized extract of maritime pine bark (Pycnogenol, Horphag Research) plus nattokinase (12075).
• Wrinkled skin. It is unclear if oral maritime pine bark extract can reduce wrinkles or improve skin health in people with significant sun exposure. Details: A small crossover study in Chinese adults working outdoors shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg twice daily for 12 weeks improves skin hydration and reduces transepidermal water loss and skin darkening when compared with placebo (105784). More evidence is needed to rate maritime pine for these uses.

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LIKELY SAFE ...when used orally and appropriately in amounts commonly found in foods. Bilberry has Generally Recognized As Safe status (GRAS) for use in foods in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes. Bilberry fruit extracts have been used with apparent safety in clinical trials at a dose of up to 160 mg daily for up to 6 months (39,40,8139,9739,14280,35472,35510,35512,103190,104192,104195). A higher bilberry extract dose of 1.4 grams daily has been used with apparent safety for up to 4 weeks (104194). Whole bilberries or bilberry juice have also been consumed with apparent safety in quantities of 100-160 grams daily for up to 35 days (35463,91506).

POSSIBLY UNSAFE ...when the leaves are used orally in high doses or for a prolonged period. Death can occur with chronic use of 1.5 gram/kg daily (2).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in the amounts commonly found in foods. However, there is insufficient reliable information available about the safety of bilberry when used in medicinal amounts during pregnancy and lactation; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately. A standardized extract of maritime pine bark (Pycnogenol, Horphag Research) has been safely used in doses of 50-450 mg daily for up to one year (2435,2451,2462,2554,2556,7693,10214,10416,12012,14899) (15424,15521,15522,15523,15524,100359,105782). The same extract has also been used with apparent safety in a dose of 800 mg daily for 16 days (103617). A different standardized extract of maritime pine bark (Oligopin, DRT Group) has been used with apparent safety in doses of up to 150 mg daily for up to 12 weeks (105781,105783). ...when applied topically as a cream or powder. A standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 0.5% cream has been used for up to 7 days (50912). Powder from a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 100 mg has been applied to the skin daily for up to 6 weeks (50887,50896).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. A standardized extract of maritime pine bark (Pycnogenol, Horphag Research), administered in a dose of 1 mg/lb body weight daily, has been safely used in a clinical study of children aged 6-18 years for up to 3 months (13120).

PREGNANCY: POSSIBLY SAFE
when used orally during the third trimester of pregnancy. In one small clinical study, a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) has been used at a dose of 30 mg daily with apparent safety during the third trimester of pregnancy (15423). However, more evidence is needed; use cautiously or avoid using.

LACTATION:
There is insufficient reliable information available regarding the safety of maritime pine when used during lactation; avoid using.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry fruit extract might increase the risk of bleeding when taken with anticoagulant or antiplatelet drugs.  Details In vitro, animal, and clinical research suggest that anthocyanidin extracts from bilberry can inhibit platelet aggregation (16631,35455,35503,35504,35505).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry leaf or fruit extract may increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Animal research suggests that bilberry leaf extract might have blood glucose-lowering activity (1264). Also, one small clinical trial in patients with type 2 diabetes shows that taking bilberry fruit extract 470 mg as a single dose prior to an oral glucose tolerance test lowers plasma glucose levels when compared with placebo (91507).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry fruit extract might decrease levels of drugs metabolized by CYP2E1.  Details Animal research shows that exposure to small concentrations of bilberry extract in drinking water for around one month increased CYP2E1 activity by 31%. However, exposure over a 2-month period did not increase CYP2E1 activity (103191). This effect has not been reported in humans.

ERLOTINIB (Tarceva) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry fruit extract might reduce the efficacy of erlotinib.  Details In vitro research suggests that bilberry fruit extract and its constituents, delphinidin and delphinidin-3-O-glucoside, inhibit the activity of erlotinib (97031). This interaction has not been reported in humans.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, maritime pine bark extract might increase the risk of bleeding when used with antiplatelet or anticoagulant drugs.  Details Clinical research suggests that maritime pine bark extract inhibits platelet aggregation (3283,50844,50942). However, the clinical significance of this effect is unclear.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, maritime pine bark extract might increase the risk of hypoglycemia when used with antidiabetes drugs.  Details One clinical study shows that maritime pine bark extract decreases blood sugar in patients with diabetes being treated with antidiabetes agents (15522). Monitor blood glucose levels closely. Dose adjustments might be necessary.

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, maritime pine bark extract might decrease the effectiveness of immunosuppressant therapy.  Details In vitro and animal research suggests that maritime pine bark extract has immunostimulant activity (2435,2636). This effect has not been reported in humans.

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General ...Orally, bilberry fruit, juice, and extracts seem to be well tolerated.
Most Common Adverse Effects:
Orally: Dark-colored stools, flatulence, and gastrointestinal discomfort.

Gastrointestinal ...In one small clinical trial, mild-to-moderate flatulence was reported in 33% of patients taking sieved bilberries and concentrated bilberry juice (91506). However, the patients in this study had ulcerative colitis, and the study lacked a control group, limiting the validity of this finding. In another small clinical study of males with age-related cognitive impairment, temporary adverse gastrointestinal (GI) effects were reported in 13% of patients drinking a combination of bilberry and grape juice. However, the adverse GI effect rate was identical in patients drinking a placebo juice (110641). A post-marketing surveillance report of 2295 patients using bilberry extract (Tegens) found that 1% of patients complained of GI discomfort and less than 1% experienced nausea or heartburn (35500).
Theoretically, fresh bilberry fruit may have laxative effects. One clinical trial noted an increased frequency of bowel movements following the administration of a combination formulation containing aerial agrimony parts, cinnamon quills, powdered bilberry fruit, and slippery elm bark (35462). It is unclear if these effects were due to bilberry, other ingredients, or the combination.

Other ...Orally, bilberry may cause discoloration of feces and the tongue. In one study, a dark-bluish to black discoloration of both the feces and the tongue was observed following consumption of sieved bilberries and concentrated bilberry juice. In one patient, a slight discoloration of the teeth has also been observed (91506). In another study, 50% of patients reported dark green stools after taking bilberry extract 700 mg twice daily for 4 weeks (104194).

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General ...Orally and topically, maritime pine bark extract seems to be well tolerated.
Most Common Adverse Effects:
Orally: Gastrointestinal complaints, dizziness, and vertigo.

Cardiovascular ...A single case of chest pain has been reported for a patient treated with a standardized extract of maritime pine bark (Pycnogenol, Horphag Research). However, the patient had a history of myocardial infarction (50905). Another patient taking the same maritime pine bark extract experienced acute decompensation of heart failure. The patient previously has stable coronary artery disease (50929). It is not clear if either of these adverse effects were directly related to maritime pine bark extract.

Gastrointestinal ...Orally, a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) may cause gastrointestinal problems (15521,15522,17300,50891,50942). Also, mouth ulcer and bad breath have been reported in a single trial (15521).

Neurologic/CNS ...Orally, a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) may cause dizziness and severe vertigo (15521,15522,17300,50904,50933). Also, headache has been reported in a single trial (15521).

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