Resveratrol & Pycnogenol by Puritan's Pride

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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POSSIBLY EFFECTIVE

• Allergic rhinitis (hay fever). Intranasal resveratrol seems to be beneficial for reducing allergic rhinitis symptoms in adults and children. Details: Some clinical research shows that intranasal resveratrol with carboxymethyl-beta-glucan can improve symptoms of allergic rhinitis (91332,97339). One clinical study in adults with allergic rhinitis shows that using an intranasal spray containing resveratrol 0.1% three times daily for 4 weeks reduces nasal symptoms and improves quality of life scores when compared with placebo (97339). A study in children aged 4-17 years with pollen-induced allergic rhinitis shows that using an intranasal spray containing resveratrol 0.05% three times daily for 2 months improves itching, sneezing, runny nose, and nasal obstruction and reduces use of rescue medication when compared with placebo (91332).
• Obesity. Oral resveratrol seems to be beneficial for weight loss in individuals with overweight or obesity. However, it is unlikely to be beneficial for improving most metabolic parameters in this population. Details: A meta-analysis of 28 clinical trials shows that taking resveratrol decreases body weight by 0.5 kg, body mass index (BMI) by 0.17 kg/m2, and waist circumference by 0.8 cm when compared with placebo or no intervention. This analysis included studies of individuals with normal weight, overweight, and obesity, with or without type 2 diabetes, metabolic syndrome, non-alcoholic fatty liver disease, or other chronic conditions. A subgroup analysis suggests that individuals with obesity have a greater response to resveratrol. In these individuals, taking resveratrol 8-3000 mg daily resulted in an average weight reduction of 1.15 kg and a BMI reduction of 0.3 kg/m2 when compared with placebo. The greatest impact on body weight and BMI occurred with resveratrol doses of no more than 500 mg daily and treatment durations of at least 3 months (100696). One clinical trial also shows that taking resveratrol 150 mg daily for 6 months reduces glycated hemoglobin (HbA1c) by a small amount when compared with placebo in individuals with overweight or obesity but has no effect on insulin sensitivity, fat mass, or levels of fasting blood glucose, lipids, or liver enzymes (105183). Also, meta-analyses of clinical research show that resveratrol is unlikely to be beneficial for improving blood pressure or blood lipids when compared with placebo in individuals with overweight or obesity (102513,105181).

POSSIBLY INEFFECTIVE

• Cardiovascular disease (CVD). Oral resveratrol does not seem to be beneficial for CVD prevention. Details: Population research suggests that a higher dietary intake of resveratrol is not associated with a reduced risk of CVD when compared with a lower dietary intake (91334). Also, a meta-analysis of clinical research shows that taking resveratrol for up to 6 months does not improve any measures of plasma lipids, including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, or triglycerides in patients at high risk for CVD (91333). While one preliminary clinical study shows that taking resveratrol 10 mg daily for 3 months improves left ventricular function by about 1% and endothelial function when compared to baseline in patients with a history of myocardial infarction and coronary artery disease, the improvements are very small and blood pressure and markers of inflammation do not appear to be improved (91330).
• Hypercholesterolemia. Oral resveratrol does not seem to be beneficial for hypercholesterolemia. Details: A meta-analysis of clinical research shows that resveratrol is unlikely to be beneficial for improving blood lipids when compared with placebo in patients with hypercholesterolemia. In the meta-analysis, studied populations included people who are overweight or obese, as well as patients with hypertension, type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), angina, and dyslipidemia (105181). Although there was a small reduction in total cholesterol levels of approximately 7 mg/dL, resveratrol did not improve levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides (105181). Also, an analysis of results from clinical research shows that taking resveratrol for up to 6 months does not improve any measures of plasma lipids, including total cholesterol, HDL cholesterol, LDL cholesterol, or triglycerides in patients at high risk for cardiovascular disease (91333). Also, clinical research in healthy humans shows that taking resveratrol 500 mg orally daily for 30 days increases levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B (112944). Another meta-analysis identified more promising results; however, any effect on blood lipids may not be considered clinically significant. This meta-analysis included 17 clinical studies enrolling 968 participants with dyslipidemia, type 2 diabetes, coronary artery disease, overweight or obesity, or stroke. Resveratrol reduced total cholesterol by approximately 10 mg/dL, LDL by approximately 6 mg/dL, and triglycerides by approximately 9 mg/dL, but did not improve HDL, when compared with placebo. However, most of the included studies were small and utilized heterogenous dosing regimens, with doses ranging from 10-3000 mg daily for 4-48 weeks (110020).
• Metabolic syndrome. Oral resveratrol does not seem to be beneficial for metabolic syndrome. Details: A meta-analysis of clinical research shows that taking resveratrol does not improve blood pressure when compared with placebo in patients with metabolic syndrome or related disorders (102513). A similar meta-analysis shows that taking resveratrol does not improve levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, or liver enzymes. There was a small reduction in total cholesterol levels of approximately 7 mg/dL (105181). However, only 3-4 of the papers included in these meta-analyses, which included 28-31 publications, evaluated patients with metabolic syndrome. The remainder included patients with related conditions, such as overweight/obesity, type 2 diabetes, or nonalcoholic fatty liver disease (NAFLD). The mainly small or preliminary clinical studies that did evaluate patients with metabolic syndrome all show that taking resveratrol 100-1000 mg daily for 12-16 weeks does not improve blood pressure, glucose control, or plasma lipids (91331,95828,102513,105181). However, one preliminary clinical trial shows that taking resveratrol 500 mg three times daily for 3 months reduces body weight by about 4 kg, body mass index (BMI) by 1.3 kg/m2, fat mass by 2.4 kg, and waist circumference by 4 cm when compared to baseline (91331). The validity of these findings is limited by the lack of a comparator group. Also, a moderate-sized clinical trial of adults with metabolic syndrome shows that taking resveratrol 300 mg and delta-tocotrienols 500 mg daily for 24 weeks improves body weight, waist circumference, blood pressure, fasting blood glucose, triglycerides, total and HDL cholesterol, and markers of inflammation and oxidative stress when compared with placebo (112144). It is unclear if these effects are due to resveratrol, delta-tocotrienols, or the combination.
• Nonalcoholic fatty liver disease (NAFLD). Oral resveratrol does not seem to be beneficial for most metabolic symptoms of NAFLD. It is unclear if oral resveratrol is beneficial for improving steatosis. Details: Although some individual studies disagree, meta-analyses reviewing 4-6 preliminary clinical studies show that taking resveratrol does not affect liver enzyme levels, insulin resistance, blood pressure, blood lipids, body mass index (BMI), or abdominal size when compared with placebo in patients with NAFLD (95826,99048,105184). Most trials have studied doses of 300-3000 mg daily for 2-3 months; one study used resveratrol 500 mg 3 times daily for 6 months (95826,98911,99048,105184). However, one meta-analysis shows that taking resveratrol might have a small effect on levels of the inflammatory mediators C-reactive protein and tumor necrosis factor (TNF)-alpha (105184). It is not clear if resveratrol might reduce steatosis in patients with NAFLD. One preliminary clinical study shows that taking resveratrol 3000 mg daily in two divided doses for 8 weeks does not improve steatosis when compared to baseline in males with NAFLD (91327). However, another preliminary clinical study in adults with NAFLD shows that taking resveratrol 500 mg daily for 3 months, while following an energy-balanced diet and exercising, improves steatosis, but not fibrosis, insulin resistance, lipid levels, or body composition, when compared with lifestyle modifications alone (91328). The difference in these findings might be due to small study sizes, the duration of therapy, or the gender of the included patients.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if topical resveratrol is beneficial for acne. Details: Preliminary clinical research shows that applying a gel containing trans-resveratrol 1 mcg per gram to facial skin for 60 days reduces the severity of acne by about 54%, compared to only 6% for control gel (71064).
• Age-related cognitive decline. It is unclear if oral resveratrol is beneficial for age-related cognitive decline. Details: One small clinical study shows that taking resveratrol 75 mg twice daily for 14 weeks modestly improves cognitive performance and memory after menopause, but not executive function or learning, when compared with placebo (95827). Another small clinical study in healthy, older adults shows that taking resveratrol 200 mg daily for 26 weeks improves memory retention, but not delayed recall or word recognition, when compared with placebo. In this study, resveratrol capsules were formulated to also contain 320 mg of quercetin to enhance the absorption of resveratrol (102511). It is unclear if resveratrol alone would result in similar effects. Despite these positive results, conflicting research exists. A small clinical study in sedentary, overweight, elderly adults shows that taking resveratrol 300 mg daily for 90 days does not improve measures of cognitive function such as psychomotor speed, attention, executive function, learning, or memory when compared with placebo. Taking a higher dose of 1000 mg daily for 90 days modestly improves psychomotor speed, but no other cognitive measures, in these patients (98907). Another small clinical study in healthy elderly adults shows that taking resveratrol 200 mg daily for 26 weeks does not improve verbal memory when compared with placebo (98909).
• Aging skin. Although there has been interest in using oral resveratrol for aging skin, there is insufficient reliable information about the clinical effects of resveratrol for this purpose.
• Beta-thalassemia. It is unclear if oral resveratrol is beneficial for beta-thalassemia. Details: A small clinical study in patients with beta-thalassemia intermedia shows that taking micronized trans-resveratrol (Xian Tianxingjian Natural Bio-Products CO., LTD) 2000 mg with piperine (Bioprex Co.) 40 mg, with or without hydroxyurea 8-15 mg/kg, daily for 6 months does not improve hemoglobin levels or affect the need for blood transfusion when compared with taking placebo with or without hydroxyurea (98908).
• Cancer. It is unclear if dietary resveratrol is beneficial for cancer prevention. Details: Population research has found that a higher dietary intake of resveratrol is not associated with a reduced risk of cancer when compared to lower dietary intake (91334).
• Chronic obstructive pulmonary disease (COPD). Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of resveratrol 10 mg, vitamin C 180 mg, zinc 15 mg, and flavonoids 160 mg daily for 20 days followed by 10 days without supplementation, repeated for three cycles, modestly reduces symptoms of cough and sputum production in patients with mild-to-moderate COPD when compared with control (71130). It is not clear if these effects are due to resveratrol, the other ingredients, or the combination.
• Cognitive function. Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in healthy young adults shows that taking a specific supplement (Transmax by BiotiviaTM) containing trans-resveratrol 500 mg and piperine 10 mg daily for 28 days does not improve most measures of cognitive performance when compared with placebo (95834).
• Cognitive impairment. Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in a small number of patients with mild cognitive impairment shows that taking resveratrol 200 mg and quercetin 350 mg daily for 26 weeks does not improve learning and memory performance when compared with placebo (102512). However, given the small sample size, it is possible this study was inadequately powered to detect significant changes in these cognitive measures.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral resveratrol is beneficial for COVID-19. Details: A small clinical trial in outpatients with COVID-19 shows that taking resveratrol (Vita-Age) 1 gram four times daily, for 7-15 days based on symptom duration, does not reduce the rate of hospitalization, emergency room visits, or pneumonia when compared with placebo. All patients also received a single dose of Vitamin D3 (109164). This study may have been inadequately powered to detect differences between groups.
• Diabetes. Some research shows that oral resveratrol is beneficial for improving glycemic indices in patients with type 2 diabetes. However, more research is needed to determine the most effective dose or the patient population most likely to benefit. Details: Although results from individual clinical studies have been mixed (91329,95825,95832,100695,109165,109167,109170), meta-analyses of clinical research show that resveratrol modestly reduces blood glucose and glycated hemoglobin (HbA1c) levels in patients with diabetes. Studies lasted 4-24 weeks and many included patients treated with antidiabetes medications, including metformin. However, these meta-analyses have yielded differing findings regarding effective doses (91329,109165,109167,109170). One meta-analysis of clinical research in individuals aged 45 years and older shows that doses of 250-1000 mg daily modestly reduce levels of fasting blood glucose, insulin, and HbA1c, as well as insulin resistance, when compared with placebo. Doses of up to 250 mg daily are generally ineffective, and only one study used doses greater than 1000 mg daily. Although sub-analyses suggest that these benefits may be limited to individuals aged 45-59 years, the number of studies in older individuals is small and findings are unclear (109165). A second meta-analysis in adults with type 2 diabetes suggests that resveratrol doses of at least 500 mg daily were necessary for reducing levels of fasting blood glucose and insulin, as well as insulin resistance (109167). A third meta-analysis, which also included Chinese language publications, shows that doses of resveratrol of at least 1000 mg daily are needed for improved glycemic control (109170). Some studies have used a specific resveratrol product (Biotivia Bioceuticals, International SrL) (95825). Although the reasons for discrepancies between individual clinical trials are not clear, it is possible that conflicting results are related to baseline blood glucose control. Resveratrol has shown benefit in patients with diabetes that is not well-controlled at baseline (HbA1c of 8% or higher) (91329), while results are mixed in patients with diabetes that is at least moderately well-controlled prior to supplementation (HbA1c of 7% or lower) (95825,100695). It is also possible that the differences may relate to the technique used to measure outcomes. For instance, resveratrol appears to improve insulin resistance when measured by the Stumvoll insulin sensitivity index, but not by the gold-standard hyperinsulinemic-euglycemic clamp technique (95832). Resveratrol has also been evaluated for improving blood pressure, blood lipid, and liver transaminase levels in patients with type 2 diabetes. Meta-analyses of clinical trials show that resveratrol has a small, but likely clinically insignificant, effect on systolic blood pressure when compared with placebo. Two meta-analyses show similar findings for diastolic blood pressure; however, some research suggests that any benefits are limited to doses of at least 500 mg daily (102513,109167,109170). Most meta-analyses of clinical research show that resveratrol does not improve blood lipid levels (105181,109167,109170) or liver transaminase levels (105181) when compared with placebo. Other clinical research in patients with overweight and type 2 diabetes shows that taking resveratrol 1000 mg daily for 8 weeks does not affect hepatic steatosis or cardiovascular risk indices when compared with placebo (109169).
• Diabetic nephropathy. It is unclear if oral resveratrol is beneficial for diabetic nephropathy. Details: Preliminary clinical research in patients with diabetic nephropathy shows that taking resveratrol 500 mg plus losartan 12.5 mg daily for 90 days can reduce urinary albumin-to-creatinine ratios, but not serum creatinine levels or glomerular filtration rates, when compared with taking placebo and losartan. When compared to baseline, the urinary albumin-to-creatinine ratio decreased by 46 mg/gram with resveratrol and increased by 25 mg/gram with placebo (100695).
• Hypertension. It is unclear if oral resveratrol is beneficial for lowering blood pressure. Details: A meta-analysis of clinical research shows that resveratrol is unlikely to be beneficial for improving systolic or diastolic blood pressure when compared with placebo in patients with hypertension. In the meta-analysis, studied populations included people who are overweight or obese, as well as patients with hypertension, type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), stroke, and dyslipidemia (102513). More research is needed in patients with hypertension.
• Migraine headache. It is unclear if oral resveratrol is beneficial for treating migraine headache. Details: A small clinical crossover study in patients with hormonal migraine headaches shows that taking resveratrol (Veri-te Resveratrol, Evolva SA) 75 mg twice daily for 3 months does not affect headache frequency, severity, or disability when compared with placebo (109166). However, this study did not include a wash-out period between treatments, introducing the potential for carry-over effects.
• Mitochondrial myopathies. It is unclear if oral resveratrol is beneficial for increasing exercise tolerance in patients with mitochondrial myopathies. Details: A very small clinical trial in adults with mitochondrial myopathies shows that taking resveratrol (Veri-te resveratrol) 500 mg twice daily for 8 weeks does not improve exercise capacity when compared with placebo (109162). This study may have been inadequately powered to detect differences between groups.
• Osteoarthritis. It is unclear if oral resveratrol is beneficial for osteoarthritis. Details: A small clinical study in patients with mild or moderate knee osteoarthritis receiving physical therapy and meloxicam 15 mg daily shows that adding resveratrol 500 mg daily for 90 days improves pain, function, and stiffness when compared with adding placebo (98910).
• Osteopenia. It is unclear if oral resveratrol is beneficial for improving bone mineral density (BMD). Details: A meta-analysis of clinical research shows that taking resveratrol at doses of up to 1500 mg daily for 1-12 months does not increase BMD or alter bone biomarkers when compared with placebo (109163). The studies in this meta-analysis included various populations, such as postmenopausal or overweight individuals, or patients with type 2 diabetes or metabolic syndrome. However, a clinical study in healthy, postmenopausal females shows that taking fermented soy 200 mg, containing resveratrol 25 mg and equol 10mg, orally daily for 12 months increases whole-body BMD when compared with placebo. Levels of markers of bone formation, including osteocalcin and bone-specific alkaline phosphatase, are increased, and the level of deoxypyridinoline, a marker of bone resorption, is decreased (112942).
• Periodontitis. It is unclear if oral resveratrol is beneficial for periodontitis. Details: A small clinical study in individuals with chronic moderate-to-severe periodontitis who recently received non-surgical treatment for periodontitis shows that taking resveratrol 480 mg daily for 4 weeks improves plaque index when compared with placebo, but resveratrol does not seem to improve other markers of periodontitis, including pocket depth, bleeding index, clinical attachment loss, or salivary markers of inflammation (112135). The study may have been inadequately powered and too short in duration to detect a difference between the groups.
• Peritoneal dialysis. It is unclear if oral resveratrol can improve outcomes with peritoneal dialysis. Details: One clinical study shows that taking trans-resveratrol 150 mg or 450 mg daily for 12 weeks increases ultrafiltration rate and volume when compared with placebo in patients on peritoneal dialysis. The effect appears to be dose-dependent (95830).
• Polycystic ovary syndrome (PCOS). It is unclear if oral resveratrol is beneficial for PCOS. Details: Clinical research in patients with PCOS shows that taking resveratrol 1000 mg daily for 3 months results in a regular menstruation cycle length in 77% of individuals, compared with 52% of those taking placebo. The occurrence of hair loss was reduced by about 50%; however, there was no effect on hormone, metabolic, or lipid profiles. There was also a small increase in fat mass and decrease in fat-free mass, although the clinical relevance of these changes is unclear (109131). A small clinical trial in adults with PCOS shows that taking micronized trans-resveratrol (RevGenetics) 1500 mg daily for 3 months decreases levels of testosterone, but does not improve weight, lipid levels, insulin sensitivity, acne, or hirsutism, when compared with placebo (95823). A meta-analysis of 4 controlled trials of resveratrol, taken orally in doses of 800-1500 mg daily for 40 days to 3 months, shows reductions in levels of testosterone, luteinizing hormone, and dehydroepiandrosterone sulfate when compared with placebo, but no effect on follicle stimulating hormone, prolactin, thyroid stimulating hormone, C-reactive protein, insulin, sex hormone binding globulin, lipids, acne, or pregnancy rates (112943).
• Rheumatoid arthritis (RA). It is unclear if oral resveratrol is beneficial for RA. Details: A small clinical study shows that adding resveratrol 1 gram orally once daily as adjunct therapy to antirheumatic drugs for 2 months reduces the number of tender and swollen joints, as well as biomarkers of inflammation. It is not known whether resveratrol reduces joint damage when assessed using conventional radiography. Also, the most effective combination of resveratrol and antirheumatic drug is not known, since the patients in this study were taking different antirheumatic drugs at variable doses (95706).
• Sciatica. Oral resveratrol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with sciatica secondary to a herniated disk shows that taking a combination of resveratrol 50 mg with alpha-lipoic acid, acetyl-L-carnitine, and cholecalciferol orally once daily for 30 days, concurrently with a physiotherapy protocol, reduces pain and disability, and improves quality of life when compared with the physiotherapy protocol alone (112933). It is unclear if the effects are due to resveratrol, other ingredients, or the combination.
• Ulcerative colitis. It is unclear if oral resveratrol is beneficial for ulcerative colitis. Details: Preliminary clinical research shows that taking trans-resveratrol (Sumabe Company) 500 mg daily for 6 weeks reduces subjective measures of disease activity and improves quality of life measures when compared with placebo in patients with mild to moderate active ulcerative colitis (95831). More evidence is needed to rate resveratrol for these uses.

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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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LIKELY SAFE ...when used in amounts found in foods (2030).

POSSIBLY SAFE ...when taken orally in doses of up to 1500 mg daily for up to 3 months (71066,71097,91328,91331,95825,95833,98910,100695,105183,109163,109167). Higher doses of 2000-3000 mg daily have been well tolerated when taken for 2-6 months, but are more likely to cause gastrointestinal side effects (91327,98908). ...when used topically for up to 30 days (71064). ...when used as an intranasal spray for up to 4 weeks (97339).

CHILDREN: LIKELY SAFE
when used in amounts found in foods.

CHILDREN: POSSIBLY SAFE
when used as an intranasal spray for up to 2 months in children 4 years of age and older (91332). There is insufficient reliable information available about the safety of resveratrol when used by mouth in larger amounts as medicine.

PREGNANCY AND LACTATION: LIKELY SAFE
when used in amounts found in foods (2030). Resveratrol is found in grape skins, grape juice, wine, and other food sources. However, wine should not be used as a source of resveratrol during pregnancy and lactation.

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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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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Resveratrol may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Resveratrol seems to have antiplatelet effects (2949,2950,2951,2952,2961,70813,70828,70831,70892,70968,71106).

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP1A1.  Details In vitro research shows that resveratrol can inhibit CYP1A1 enzymes (70811,70862). However, this interaction has not been reported in humans.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP1A2.  Details In vitro research shows that resveratrol can inhibit CYP1A2 enzymes (21733). However, this interaction has not been reported in humans.

CYTOCHROME P450 1B1 (CYP1B1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP1B1.  Details In vitro research shows that resveratrol can inhibit CYP1B1 enzymes (70834). However, this interaction has not been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP2C19.  Details In vitro research shows that resveratrol can inhibit CYP2C19 enzymes (70896). However, this interaction has not been reported in humans.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Resveratrol might increase levels of drugs metabolized by CYP2E1.  Details In vitro research suggests that resveratrol inhibits CYP2E1 isoenzyme (7864,70896). Also, a pharmacokinetic study shows that taking resveratrol 500 mg daily for 10 days prior to taking a single dose of chlorzoxazone 250 mg increases the maximum concentration of chlorzoxazone by about 54%, the area under the curve of chlorzoxazone by about 72%, and the half-life of chlorzoxazone by about 35% (95824). Chlorzoxazone is used as a probe drug for CYP2E1.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, resveratrol might increase levels of drugs metabolized by CYP3A4.  Details In vitro research shows that resveratrol can inhibit the CYP3A4 enzyme (7864,70896). However, clinical research shows that taking resveratrol 3000 mg daily for 8 weeks does not necessitate dose adjustments to medications metabolized by CYP3A4 (91327).

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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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General ...In foods, resveratrol is well tolerated. When used orally in higher doses, as well as topically or intranasally, resveratrol seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal discomfort, and loose stools.

Dermatologic ...Orally, there is one case of a pruritic skin rash that occurred in a clinical trial. The rash resolved two weeks after stopping resveratrol (109163).
Topically, a case of allergic contact dermatitis has been reported after applying a facial cream (Resveratrol BE, Skinceuticals) containing aqueous resveratrol 1% in combination with Baikal skullcap root extract 0.5%. Patch testing identified a positive reaction to both ingredients (110024).

Gastrointestinal ...Orally, mild gastrointestinal discomfort with increased diarrhea or loose stools has been reported, especially when resveratrol is taken in doses of 2. 5-5 grams daily (71042,71052,91327,95830,109163,109164,109167).

Hematologic ...In one clinical study, a patient developed severe febrile leukopenia and thrombocytopenia after taking oral resveratrol 500 mg three times daily for 10 days. Upon re-exposure to resveratrol, febrile leukopenia recurred (109163).

Musculoskeletal ...Orally, resveratrol has been associated with muscle cramps in patients on peritoneal dialysis. The causality of this adverse effect has not been established (95830).

Neurologic/CNS ...Orally, resveratrol has been associated with headache, fatigue, and memory loss in patients on peritoneal dialysis. The causality of these adverse effects has not been established (95830).

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