Go Easy by Dr. Mercola

POSSIBLY EFFECTIVE

• Urinary tract infections (UTIs). Cranberry products may possibly reduce the risk of repeat, symptomatic UTI in females with recurrent UTI, in children, and in people susceptible to UTI following kidney transplant, urogenital surgery, or radiation therapy near the urogenital system. While some positive evidence exists, most research suggests that cranberry products do not seem to reduce the risk of UTI in older adults in institutions, pregnant patients, or adults with neuromuscular dysfunction of the bladder. Cranberry is not recommended for the treatment of UTI in any population. Details: Cranberry appears to reduce the risk of UTI in some populations but not others. In healthy females at an increased risk of UTI or history of recurrent UTI, meta-analyses of clinical trials show that cranberry products decrease the overall risk of recurrent or first-time UTI by 26% to 35% (46473,92578,96739,111407). In 2019, the American Urological Association published guidelines stating that, based on low certainty evidence, clinicians may offer cranberry tablets or juice as prophylaxis for females with recurrent UTIs. Due to a lack of compelling evidence for any specific product, the guidelines recommend choosing formulations based on availability and tolerability (100855). In 2020, the US Food and Drug Administration (FDA) approved qualified health claims stating that consuming cranberry juice in doses of at least 8 ounces daily, or cranberry supplements in doses of at least 500 mg daily, may help reduce the risk of recurrent UTI in healthy females. However, the FDA has concluded that there is limited scientific evidence to support these claims (103302). The benefits of cranberry for prevention of UTI during pregnancy are unclear. Subgroup analysis of meta-analyses suggest that cranberry supplementation does not reduce the risk of UTI in pregnant adults compared with placebo or no treatment (100855,111407). A preliminary clinical study shows that drinking cranberry juice 240 mL three times daily until delivery does not reduce the frequency of asymptomatic bacteriuria or symptomatic UTI during pregnancy, although the study was not adequately powered to detect a difference in these outcomes (16415). In contrast, one preliminary clinical trial shows that UTI frequency was reduced in 70.5% of those ingesting cranberry juice 250 mL four times daily, compared with only 32% of those taking placebo (93670). In children, a meta-analysis shows that taking cranberry products probably reduces the risk of subsequent symptomatic UTIs by up to 54% compared with placebo or no treatment, but does not specify a particular formulation (111407). Clinical trials show that daily consumption of cranberry syrup (Pharmatoka), cranberry juice (Cranberry UR-50, Kikkoman Company) 100 mL, cranberry-lingonberry juice 50 mL, and cranberry extract (Anthocran) 120 mg reduce the risk of UTI recurrence in children (46452,96733,96737,108055). In contrast, another clinical trial shows that drinking cranberry juice (Ocean Spray Cranberries, Inc) 5 mL/kg daily for 6 months does not reduce the incidence of recurrent UTI when compared with placebo, although it does decrease the total number of UTI episodes and length of antimicrobial therapy per child (46470). In older, institutionalized adults, a meta-analysis of 5 studies evaluating the effectiveness of cranberry products shows little or no benefit in preventing symptomatic, culture-verified UTIs (111407). A clinical study in females residing in long-term care (LTC) facilities shows that taking a specific cranberry supplement (Ellura, Pharmatoka) once daily for 1 year does not reduce the incidence of UTI or asymptomatic bacteriuria (92517). However, clinical trials of cranberry products in elderly patients in LTC facilities suggest that cranberry may be more effective in patients at a higher risk for UTIs, such as those with diabetes, long-term catheterization, or recurrent UTIs (90041,108055), and in patients with E. coli-related UTIs (46389,46472). In one small study, providing all patients living in a LTC facility with 4 ounces of cranberry juice or six tablets of a specific concentrated cranberry product (Azo-Cranberry, i-Health, Inc.) daily for 13 months decreased the facility's overall monthly UTI rate from 27.7 to 20.7 (46492). In another clinical trial, taking cranberry juice cocktail (Ocean Spray Cranberries, Inc) 300 mL daily for 6 months decreased the rate of asymptomatic bacteriuria plus pyuria by 13% in older females living in institutional settings (7008). In another clinical trial, taking a cranberry capsule 500 mg, standardized to 1.8% PACs, twice daily for 12 months decreased the risk of UTI by around 26% in patients at high-risk for UTI, including those with catheters, diabetes, or at least one UTI in the previous 12 months (90041). Meta-analyses and clinical research show that cranberry products do not reduce the risk of UTI associated with neurogenic bladder, neuromuscular dysfunction, or insufficient bladder emptying in adults or children (2811,6759,11980,46379,46425,46473,90044,92578,96737,108055,111407). However, one study found benefit in patients with neurogenic bladder due to spinal cord injury taking cranberry capsules (Cran-Max, Proprietary Nutritionals, Inc.) 500 mg daily (46443). Cranberry products have also been evaluated in a variety of other high-risk populations, with mixed results. A meta-analysis of 7 studies shows that cranberry products reduce the risk of UTIs in people with increased susceptibility to UTI due to an intervention (e.g., kidney transplant, radiotherapy to urogenital system, or urogenital surgery) when compared with placebo (111407). Cranberry extracts do not seem to reduce the risk of UTIs in individuals undergoing hysterectomy and/or anterior vaginal repair (46465), pelvic floor surgery (104245), or in patients with multiple sclerosis (46496,111407). Taking cranberry powder capsules (NurtiCran90, Petefa AB) 550 mg three times daily for 5 days does not reduce the UTI rate at days 5 or 14 when compared with placebo in postoperative females with hip fracture receiving a urinary catheter; however, the study was not adequately powered to detect a difference in this outcome (96734). Other preliminary clinical research in elderly males with benign prostatic hyperplasia and a recent UTI shows that taking a standardized cranberry extract (Anthocran) 120 mg daily for 60 days reduces the UTI recurrence rate by about 62% when compared with placebo (96735). Cranberry supplements have been studied in a variety of formulations, but it is unclear whether certain cranberry formulations are better than others (111407). Most positive studies utilized oral cranberry EXTRACTS in tablet, powder, or capsule form (6760,17210,46366,46432,93669,111407). Some products (Cranberry Supreme, GNC; Cranpac, IPCA Laboratories), taken as 200 mg twice daily, were standardized to provide 100-120 mg of proanthocyanidins (PACs) daily (46432). Some of these studies used capsules containing 400 mg cranberry solids twice daily (6760) or Natural Cranberry Extract (Solgar Vitamin and Herb Co.) 800 mg twice daily (17210). However, a clinical study in healthy females with a history of UTIs shows that taking a specific cranberry extract product (Urophenol; Diana Food) does not reduce the risk of symptomatic UTI when taken at a dose of 120 mg twice daily, standardized to 15% PACs, or at a dose of 1 mg twice daily, standardized to 1% PACs. A subgroup analysis suggests that the high dose may have modest benefit in those with less than 5 UTIs a year (108054). Cranberry JUICE or syrup has yielded mixed results for the prevention of UTI in patients with a history of recurrent UTIs, with some showing significant benefit (8253,46366,96736,111407). These studies used cranberry juice 240-250 mL 1-3 times daily (46366,96736), cranberry syrup, or a combination beverage containing cranberry juice plus lingonberry juice (Maija) 50 mL daily (8253). However, other studies found no significant improvement when compared with placebo (17524,46471,90047), although some of these studies may have been inadequately powered to detect a difference (17524,46471). Cranberry products have also been compared with other treatments including antibiotics and probiotics for preventing recurrent UTI, but the results are unclear. A meta-analysis suggests that cranberry products reduce the risk of symptomatic UTIs compared to probiotics. The analysis also showed no difference in the risk of UTI between cranberry products and antibiotics, but the precision of included studies was poor (111407). In one study, taking cranberry extract capsules (Cran-Max; Proprietary Nutritionals, Inc) 500 mg daily for 6 months was as effective as trimethoprim 100 mg daily in elderly females with recurrent UTI (16720). However, taking this same cranberry product twice daily for 12 months was less effective than trimethoprim-sulfamethoxazole 480 mg once daily in younger premenopausal individuals (17176). Additional research in children with vesicoureteral reflux (VUR) shows that daily consumption of cranberry products results in UTI recurrence rates equivalent to those obtained with prophylactic antibiotics. Cranberry juice (Cranberry UR-50, Kikkoman Company) 100 mL daily was equally effective to cefaclor 5-10 mg/kg daily; cranberry syrup (Pharmatoka) 0.2 mL/kg daily was equally effective to trimethoprim 0.2 mL/kg daily (96737).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral cranberry is beneficial for age-related cognitive decline. Oral cranberry may be beneficial for improving visual episodic memory in healthy, elderly adults, but its effects on other aspects of cognition are unclear. Details: A clinical study in healthy adults aged 50-80 years shows that taking a freeze-dried cranberry powder 4.5 grams twice daily (standardized to provide 281 mg proanthocyanidins daily), provided as a sachet and added to food or beverage for 12 weeks, improves visual episodic memory performance during a memory and recall test (Rey Complex Figure Test), but does not appear to affect other measures such as attention, orientation, fluency, language, processing speed, or short-term memory, when compared with placebo (108564). Cranberry supplementation also does not appear to affect grey matter structure; however, due to the low number of patients who completed a baseline and follow-up MRI, this study may not have been adequately powered to detect a difference between groups.
• Benign prostatic hyperplasia (BPH). Preliminary clinical research suggests that oral cranberry is beneficial for reducing BPH symptoms. Details: Preliminary clinical research shows that taking powdered dried cranberry fruit 500 mg three times daily for 6 months improves lower urinary symptoms and reduces prostate specific antigen (PSA) levels when compared with no treatment in patients 45 years of age or older with elevated PSA levels, a negative prostate biopsy, and clinically confirmed non-bacterial prostatitis (17126). Another small study in those 45 years of age and older without elevated PSA levels shows that taking a specific dried cranberry powder (Flowens, Naturex-DBS, LLC) 250-500 mg daily for 6 months reduces lower urinary tract symptoms and improves voiding and storage symptoms when compared with placebo (96738).
• Cancer. Although there has been interest in using oral cranberry for cancer, there is insufficient reliable information about the clinical effects of cranberry for this condition.
• Cardiovascular disease (CVD). Although some research suggests that oral cranberry may modestly improve some CVD risk factors, it is unclear if it is beneficial for CVD prevention. Details: A meta-analysis of 10 clinical studies shows that cranberry juice or cranberry extract seems to reduce systolic blood pressure by 3.6 mmHg and body mass index by 0.3 kg/m2 when compared with placebo. However, these improvements are unlikely to be clinically significant, and cranberry does not appear to improve diastolic blood pressure, lipid levels, glycemic control, or waist circumference (102849). The generalizability of these results is limited, as the study populations ranged from healthy adults to those with type 2 diabetes, metabolic syndrome, or coronary heart disease. A clinical crossover study in patients who are overweight or obese and have elevated blood pressure shows that drinking cranberry juice 250 mL twice daily for 8 weeks reduces ambulatory diastolic blood pressure by 2 mmHg during daytime hours, but does not improve systolic blood pressure, glycemic control, or lipid levels, when compared with placebo (108059). The validity of these findings is limited due to short duration of treatment and broad heterogeneity of patient baseline characteristics.
• Catheter-related infections. Although there has been interest in using oral cranberry for catheter-related infections, there is insufficient reliable information about the clinical effects of cranberry for this condition.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral cranberry for CFS, there is insufficient reliable information about the clinical effects of cranberry for this condition.
• Diabetes. It is unclear if oral cranberry is beneficial for diabetes. Details: A small clinical trial shows that taking cranberry supplements orally does not improve fasting serum glucose, glycated hemoglobin (HbA1C), fructosamine, triglycerides, high-density lipoprotein (HDL) cholesterol, or low-density lipoprotein (LDL) cholesterol levels in patients with type 2 diabetes (11328).
• Helicobacter pylori. There is conflicting evidence regarding the use of oral cranberry for Helicobacter pylori eradication, either as a standalone treatment or in combination with standard triple therapy. Details: Two small clinical studies show that taking cranberry juice 480-500 mL, containing 88 mg proanthocyanidins (PACs), daily in two divided doses for 2-3 months can modestly increase the H. pylori eradication rate at 8 weeks, but not at 2 weeks, when compared with placebo. However, the eradication rate was only 20% or less, which is much lower than that obtained with conventional triple therapy (46388,104248). Lower doses, as either cranberry juice or cranberry powder, do not seem to improve H. pylori eradication rates. Cranberry juice containing only 23 mg or 44 mg PACs or cranberry powder containing 36 mg or 72 mg PACs did not demonstrate benefit when compared with placebo (104248). Cranberry juice has also been studied in combination with standard triple therapy. Preliminary clinical research shows that taking cranberry juice 250 mL daily for 3 weeks along with omeprazole, amoxicillin, and clarithromycin for one week does not increase the eradication rate when compared with triple therapy plus placebo. However, the combination treatment increased the rate of H. pylori eradication when only females were considered (46439). A meta-analysis of 4 small clinical studies, including three studies already discussed, shows that taking cranberry, either as a juice or a dried powder, does not improve H. pylori eradication rate when compared with placebo, regardless of treatment duration (108060). The validity of these findings is limited by the high heterogeneity of the included studies and incomplete reporting. In asymptomatic children aged 6-16 years old with H. pylori, one clinical study shows that drinking cranberry juice 200 mL, with live or heat-killed Lactobacillus johnsonii 80 mL, daily for 3 weeks eradicates H. pylori in 15% to 22% of patients, compared with 1.5% of those receiving placebo. However, these rates are lower than those typically obtained with conventional triple therapy (46441).
• Hyperlipidemia. Oral cranberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Drinking a combination of cranberry, blueberry, apple, and chokeberry juice 300 mL daily for 6 weeks appears to decrease total cholesterol and increase high-density lipoprotein (HDL) cholesterol when compared to baseline in females with overweight or obesity and at least one risk factor for cardiovascular disease (111233). However, the validity of the study is limited by its small size, short duration, and lack of a comparator group. It is unclear if these effects are due to cranberry, other ingredients, or the combination.
• Kidney stones (nephrolithiasis). It is unclear if oral cranberry is beneficial for reducing the risk of kidney stones. Details: Although some preliminary clinical research shows that drinking cranberry juice 500 mL diluted in 1500 mL water daily for 2 weeks can decrease urinary excretion of oxalate in healthy males, which suggests a decreased risk of kidney stone formation (46371), other preliminary clinical research shows that both cranberry juice and concentrated cranberry extracts can increase urinary oxalate levels, suggesting an increased risk of stone formation (7074,46393).
• Memory. It is unclear if oral cranberry is beneficial for memory. Details: Preliminary clinical research in cognitively intact older adults shows that taking cranberry juice 16 ounces twice daily for 6 weeks does not improve memory when compared with placebo (46390).
• Metabolic syndrome. It is unclear if oral cranberry is beneficial for metabolic syndrome. Details: Preliminary clinical research shows that drinking cranberry juice 240 mL twice daily for 8 weeks can increase plasma antioxidant capacity when compared with placebo in adults with metabolic syndrome. However, cranberry juice does not appear to affect blood pressure, blood glucose, serum lipids, or markers of inflammation when compared with placebo in these patients (46467).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral cranberry is beneficial for NAFLD. Details: Preliminary clinical research in adults with NAFLD shows that adding cranberry extract 288 mg daily to a weight loss diet for 12 weeks does not appear to affect body weight, liver enzymes, lipid levels, or steatosis grade when compared with placebo. Cranberry extract may moderately reduce insulin levels and insulin resistance (104249). However, the clinical impact of these reductions is unclear. Another clinical trial in adults with NAFLD shows that taking dried cranberry powder 144 mg daily after lunch for 6 months improves steatosis grade as measured by ultrasound, insulin sensitivity, and levels of total cholesterol and triglycerides, but does not affect liver enzyme levels, when compared with placebo. All patients also consumed a reduced-calorie diet and an undefined dose of supplemental vitamin E (108058).
• Obesity. Oral cranberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with overweight or obesity and at least one risk factor for cardiovascular disease shows that drinking a combination of cranberry, blueberry, apple, and chokeberry juice 300 mL daily for 6 weeks does not reduce body weight, body mass index (BMI), or blood pressure but might improve total cholesterol and high-density lipoprotein (HDL) cholesterol when compared to baseline (111233). However, the validity of these findings is limited by the small study size, short duration, and lack of a comparator group. It is unclear if these effects are due to cranberry, other ingredients, or the combination.
• Overactive bladder. It is unclear if oral cranberry is beneficial for overactive bladder. Details: Preliminary clinical research in otherwise healthy females shows that taking dried cranberry powder 500 mg daily for 24 weeks can reduce daily micturition by 16% and urgency episodes by 57% when compared with placebo. Patients taking cranberry powder also reported an improvement in their own perception of their bladder condition when compared with placebo (104246). Limitations of this study include a short duration, lack of a run-in period, and high drop-out rate, which interfered with the ability to meet power.
• Peristomal lesions. Although there has been interest in using oral cranberry for peristomal lesions, there is insufficient reliable information about the clinical effects of cranberry for this condition.
• Prostate cancer. It is unclear if cranberry is beneficial for preventing prostate cancer recurrence. Details: Clinical research shows that taking cranberry powder (Pacran, Naturex) 1500 mg for a mean of 30 days prior to radical prostatectomy for prostate cancer does not improve prostate tissue markers when compared with taking placebo. However, levels of prostate tissue antigen decreased by approximately 22% when compared with baseline (105127).
• Radiation-induced cystitis. Evidence for the use of cranberry juice in the prevention of radiation-induced cystitis is conflicting. Details:One small clinical study in individuals with prostate cancer shows that taking 200 mg of a cranberry extract standardized to 30% proanthocyanidins (Monoselect Macrocarpon; PharmExtracta) once daily during external beam radiotherapy for 6-7 weeks reduces the risk of lower UTI by 64% when compared with placebo (92579). However, other preliminary clinical research shows that taking cranberry capsules, standardized to contain a total of 72 mg proanthocyanidins, daily during radiation treatment for prostate cancer and for two weeks post-treatment, does not improve pain, burning, nocturia, or urinary flow symptoms from radiation-induced cystitis when compared with a beetroot placebo (104247). Additionally, preliminary clinical research in patients receiving radiotherapy for bladder or cervical cancer shows that consuming cranberry juice 250 mL daily for 2 weeks does not seem to reduce the incidence of UTIs (46469).
• Rheumatoid arthritis (RA). It is unclear if cranberry juice is beneficial in RA. Details: A clinical study in adults with RA shows that drinking reduced-calorie cranberry juice 250 mL twice daily in addition to taking fish oil 1 gram three times daily for 90 days improves disease activity score (DAS28-CRP) when compared with no supplementation. However, this combination was similarly effective to patients taking fish oil alone, suggesting that any benefits may be due to fish oil, as opposed to cranberry juice (108057).
• Upper respiratory tract infection (URTI). It is unclear if oral cranberry is beneficial for the prevention or treatment of URTIs. Details: Clinical research shows that drinking a cranberry juice beverage 450 mL daily for 70 days does not decrease the incidence of cold or flu, but may reduce cold and flu symptoms, when compared with placebo in healthy adults (90046).
• Urinary odor. It is unclear if oral cranberry is beneficial for urinary odor. Details: Preliminary clinical research shows that cranberry juice cocktail might reduce urinary odors when given orally on a regular basis to patients with urinary incontinence (3333,3334,8254). Cranberry juice cocktail up to 237 mL three times daily for up to 4 weeks has been used (3334). More evidence is needed to rate cranberry for these uses.

(Read more about CRANBERRY)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dyspepsia. Oral olive leaf extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in healthy adults shows that taking a specific combination product containing olive leaf extract 24% and prickly pear cactus 33% (Mucosave, Bionap S.R.L.) 400 mg daily for 8 weeks seems to improve dyspepsia and other gastrointestinal symptoms when compared with placebo (105904). It is unclear if this benefit would occur in patients with clinically diagnosed dyspepsia.
• Exercise-induced respiratory infections. It is unclear if oral olive leaf extract is beneficial for reducing respiratory infections from exercise. Details: A small clinical study in high school athletes shows that taking one tablet of olive leaf extract providing eleuropein 100 mg daily for 2 months during training season does not reduce the incidence of the common cold when compared with placebo. While it may reduce the number of sick days by 28%, a sub-group analysis suggests that this reduction is only evident in female athletes (101860).
• Gastroesophageal reflux disease (GERD). Although there is interest in using oral olive leaf for GERD, there is insufficient reliable information about the clinical effects of olive for this condition.
• Herpes zoster (shingles). Although there is interest in using oral olive leaf for shingles, there is insufficient reliable information about the clinical effects of olive for this condition.
• Influenza. Although there is interest in using oral olive leaf for influenza, there is insufficient reliable information about the clinical effects of olive for this condition.
• Metabolic syndrome. It is unclear if oral olive leaf extract is beneficial for improving body composition and cardiovascular risk factors in patients with metabolic syndrome. Details: A small clinical trial in overweight, middle-aged males at risk for metabolic syndrome shows that taking four capsules of olive leaf extract providing oleuropein 51.1 mg and hydroxytyrosol 9.7 mg daily for 12 weeks improves insulin sensitivity by 15% when compared with placebo. However, body composition, blood pressure, cholesterol levels, and other cardiovascular risk factors were not improved (92245).
• Osteoarthritis. It is unclear if oral olive fruit or leaf extract is beneficial for improving osteoarthritis. Details: Preliminary clinical research shows that taking a freeze-dried aqueous extract of olive fruit 400 mg daily for 8 weeks decreases pain and increases mobility in people with osteoarthritis (14844). Other preliminary clinical research in adults with knee osteoarthritis shows that taking olive leaf extract 50.1 mg daily for 4 weeks improves overall pain measurements by 14%, compared to only 4% in the placebo group. However, many individual measurements of pain are not improved (92252).
• Osteoporosis. It is unclear if oral olive leaf extract is beneficial for osteoporosis. Details: Clinical research shows that taking olive leaf extract (Bonolive, BioActor BV) 250 mg daily for 12 months, along with elemental calcium 400 mg daily, increases osteocalcin levels by about 32% when compared to baseline; this increase was significant when compared to those taking calcium 400 mg plus placebo, who showed a 6% decrease in osteocalcin levels. However, taking olive leaf extract does not significantly increase bone mineral density of the lumbar spine or femur neck when compared with placebo (92247).
• Rheumatoid arthritis (RA). It is unclear if oral olive fruit extract is beneficial for improving RA symptoms. Details: Preliminary clinical research in adults with RA shows that taking an aqueous freeze-dried extract of olive fruit 400 mg daily for 8 weeks does not improve symptoms when compared with control (14844). More evidence is needed to rate the effectiveness of olive for these uses.

(Read more about OLIVE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral perilla is beneficial in patients with age-related cognitive decline. Details: Preliminary clinical research in healthy elderly adults shows that taking perilla seed oil 7 mL orally daily for 12 months does not improve cognitive function scores when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (110612). Other preliminary clinical research in healthy adults at least 60 years of age shows that taking perilla seed oil 1.47 mL orally daily for 12 months does not improve cognitive function scores when compared with baseline. However, taking perilla seed oil 1.47 mL plus ponkan powder 1.12 grams modestly improved cognitive function scores (110615).
• Allergic rhinitis (hay fever). It is unclear if oral perilla is beneficial in patients with allergic rhinitis. Details: Preliminary clinical research in patients with seasonal allergic rhinoconjunctivitis shows that taking perilla extract 50 or 200 mg orally daily for 21 days decreases symptoms such as itchy nose, watery eyes, itchy eyes, and total symptoms when compared with placebo (68658).
• Asthma. It is unclear if oral perilla is beneficial in patients with asthma. Details: Two very small clinical studies in adults with mild asthma show that taking perilla seed oil 10-20 grams orally daily for 4 weeks modestly improves peak expiratory flow, forced vital capacity, and forced expiratory volume in 1 second when compared with baseline and placebo (1338,65485).
• Cancer. Although there has been interest in using oral perilla for cancer, there is insufficient reliable information about the clinical effects of perilla for this purpose.
• Canker sores. It is unclear if oral perilla is beneficial in patients with canker sores. Details: Preliminary clinical research in patients with recurrent canker sores shows that using perilla seed oil as the only type of cooking oil for 8 months does not decreases the incidence of canker sores any better than using soybean oil (68676).
• Common cold. Although there has been interest in using oral perilla for the common cold, there is insufficient reliable information about the clinical effects of perilla for this purpose.
• Constipation. It is unclear if oral perilla is beneficial in patients with constipation. Details: Preliminary clinical research shows that taking a specific perilla leaf extract (Benegut, Vital Solutions GmbH) 150 mg orally twice daily for 4 weeks does not improve bloating, abdominal discomfort, gas, feelings of fullness, or stool frequency when compared with placebo in healthy adults who complain of gastrointestinal discomfort and reduced bowel movements (94312).
• Cough. Although there has been interest in using oral perilla for cough, there is insufficient reliable information about the clinical effects of perilla for this purpose.
• Dementia. It is unclear if oral perilla is beneficial in patients with dementia. Details: Preliminary clinical research in patients with mild to moderate dementia shows that taking perilla seed oil 1 gram orally three times daily for 6 months does not improve cognitive function when compared with placebo (101808).
• Depression. Although there has been interest in using oral perilla for depression, there is insufficient reliable information about the clinical effects of perilla for this purpose.
• Headache. Although there has been interest in using oral perilla for headache, there is insufficient reliable information about the clinical effects of perilla for this purpose.
• Nausea and vomiting. Although there has been interest in using oral perilla for nausea and vomiting, there is insufficient reliable information about the clinical effects of perilla for this purpose.
• Osteoporosis. Although there has been interest in using oral perilla for osteoporosis, there is insufficient reliable information about the clinical effects of perilla for this purpose. More evidence is needed to rate perilla for these uses.

(Read more about PERILLA)

LIKELY EFFECTIVE

• Intermittent claudication. Oral use of policosanol can increase walking distance in patients with intermittent claudication. Details: Multiple, small, randomized controlled trials show that taking policosanol 10 mg orally once to twice daily for up to 2 years moderately improves walking distance when compared with placebo, lovastatin, or aspirin, and has similar effects to ticlopidine, in patients with intermittent claudication (2931,65359,65372,65378,69114).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angioplasty. It is unclear if oral policosanol is beneficial for patients after angioplasty. Details: Preliminary clinical research has evaluated the addition of policosanol to dual antiplatelet therapy in Chinese patients with high on-treatment platelet reactivity (HPR) who underwent percutaneous coronary intervention with a drug-eluting stent for an acute coronary syndrome. The addition of policosanol 40 mg orally daily with clopidogrel 75 mg daily and aspirin 300 mg daily for 30 days does not further reduce HPR when compared with taking clopidogrel and aspirin alone (100684).
• Coronary heart disease (CHD). It is unclear if oral policosanol is beneficial for patients with CHD. Details: One small clinical study in adults with CHD shows that taking policosanol 5 mg twice daily, alone or in combination with aspirin 125 mg for 20 months, can reduce cardiac events and improve maximum oxygen uptake during a treadmill exercise electrocardiogram (ECG) when compared with pretreatment (2941). Policosanol has also been evaluated as part of combination products for CHD. Clinical research in statin-intolerant patients with CHD treated with a percutaneous intervention (PCI) shows that taking a specific combination product (Armolipid Plus, Rottapharm S.p.A.) containing policosanol, berberine, red yeast rice, folic acid, coenzyme Q10, and astaxanthin daily for 3 months reduces total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, and increases high-density lipoprotein (HDL) cholesterol, to a greater extent than ezetimibe 10 mg daily. Combining this specific product with ezetimibe produces additional improvements after 1 year of treatment when compared with either agent alone (97232). Other clinical research in patients with CHD treated with PCI shows that taking the same product in combination with a low-dose statin for 3 months reduces total cholesterol and LDL cholesterol and increases HDL cholesterol when compared with low-dose statin treatment alone (97233). It is unclear if the benefits of this combination product are due to policosanol, other ingredients, or the combination.
• Familial hypercholesterolemia. It is unclear if oral policosanol is beneficial for patients with familial hypercholesterolemia. Details: Preliminary clinical research shows that taking a specific form of policosanol (Lesstanol Octa-60, Garuda International) 20 mg orally daily for 12 weeks does not significantly decrease total or low-density lipoprotein (LDL) cholesterol in patients with familial hypercholesterolemia (14404).
• Hypercholesterolemia. It is unclear if oral policosanol is beneficial for patients with hypercholesterolemia. Details: Current clinical research on the use of policosanol for hyperchloremia is conflicting. The reasons for these discrepant findings are unclear but may be explained by differences in doses, treatment durations, patient populations, and specific policosanol products studied. Clinical research in subjects with hypercholesterolemia, largely conducted by researchers in Cuba, shows that taking policosanol orally 5-20 mg daily for 8-24 weeks lowers total cholesterol by 9% to 29% and low-density lipoprotein (LDL) cholesterol by 11% to 42% and increases high-density lipoprotein (HDL) cholesterol by 7% to 34% when compared with placebo or other controls (2927,2928,2929,2930,2943,2944,14298,14411,65348,65354)(65355,65356,65361,65363,65365,65369,65375,65380,65383,69104)(69105,69106,65362,65351,100178). When compared to conventional drugs, some research also shows that policosanol 10 mg daily lowers total and LDL cholesterol by a similar amount as fluvastatin 20 mg daily and simvastatin 10 mg daily (8147,12190). Atorvastatin 10 mg daily appears to be more effective than policosanol 10 mg daily for lowering total and LDL cholesterol (14411). However, the majority of research conducted outside of Cuba has been contradictory. Research in subjects with hypercholesterolemia, conducted by German, Canadian, Croatia, South African, Netherlands, U.S., and Italian researchers, shows that taking policosanol 10-80 mg daily for 4-12 weeks does not significantly decrease total or LDL cholesterol when compared with placebo (14336,15062,69111,69119,69107,69109,69110,12166,14404). These studies included policosanol derived from Cuban sugar cane, U.S. sugar cane, wheat germ, and red yeast rice and specific policosanol products (Lesstanol Octa-60, Garuda International; Cholesstor, Pharmed Group) (69107,69109,69110,12166,14404). Policosanol has also been studied in combination with other ingredients. Taking a product containing policosanol 10 mg, berberine 500 mg, and red yeast rice 200 mg daily for up to 12 months seems to reduce total cholesterol and LDL cholesterol levels in hypercholesterolemic patients when compared with placebo or ezetimibe 10 mg (34262,34283,34301). Taking a specific combination product (Armolipid Plus, Rottapharm S.p.A.) containing policosanol, berberine, red yeast rice, folic acid, coenzyme Q10, and astaxanthin daily for 8 weeks appears to reduce total cholesterol by 13% and LDL cholesterol by 21%, as well as increasing HDL cholesterol by 5% when compared with baseline in patients with metabolic syndrome and dyslipidemia (89438). A meta-analysis also shows that taking this combination product for up to 1 year reduces total cholesterol by 10%, LDL cholesterol by 14%, and triglycerides by 7%, and increases HDL cholesterol by 4%, when compared with baseline in patients with hypercholesterolemia (92142). It is unclear if the benefits of this combination product are due to policosanol, red yeast rice (which contains monacolin K, a chemical similar to lovastatin), other ingredients, or the combination.
• Hypertension. It is unclear if oral policosanol is beneficial for patients with hypertension. Details: Clinical research in adults with prehypertension shows that taking policosanol 20 mg orally daily for 12 weeks reduces both systolic and diastolic blood pressure by about 7%, compared to non-significant changes with placebo. A lower dose of policosanol 10 mg daily did not improve blood pressure when compared with placebo (100177).
• Metabolic syndrome. Oral policosanol has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific combination product (Armolipid Plus, Rottapharm S.p.A.) containing policosanol, berberine, red yeast rice, folic acid, coenzyme Q10, and astaxanthin daily for 18 weeks improves systolic blood pressure, left ventricular mass, and flow-mediated dilation in patients with metabolic syndrome when compared with control (34289). It is unclear if these effects are due to policosanol, other ingredients, or the combination. More evidence is needed to rate policosanol for these uses.

(Read more about POLICOSANOL)

EFFECTIVE

• Ariboflavinosis. Oral riboflavin can treat and prevent low riboflavin levels.

POSSIBLY EFFECTIVE

• Hyperhomocysteinemia. Oral riboflavin reduces homocysteine levels in individuals with the MTHFR 677 TT genotype. It does not seem to provide benefit in individuals with other genotypes. Details: Population research has found that poor riboflavin status is associated with high homocysteine levels in individuals with the 677 TT genotype for the MTHFR enzyme (71386,71403,71409). Taking riboflavin 1.6 mg daily for 12 weeks reduces homocysteine levels by 22% to 40% in individuals with the 677 TT genotype of MTHFR when compared with pretreatment. However, riboflavin supplementation does not seem to reduce homocysteine levels in individuals with the 677 CC or CT genotypes (71443).
• Migraine headache. Oral riboflavin modestly reduces migraine attack frequency and severity in adults. The benefits of oral riboflavin in children are unclear. Details: A meta-analysis of 5 small clinical trials in adults with migraine shows that taking riboflavin 100-400 mg daily, alone or in combination with other natural ingredients, for three months modestly reduces migraine duration, frequency, and pain scores when compared with control (105480). These findings are limited by significant heterogeneity. Most clinical studies compared riboflavin 400 mg daily with placebo, no treatment, or an active control (1396,1397,1398,12387,105480). Limited evidence also suggests that taking riboflavin 400 mg daily might be no different for migraine prevention than certain conventional treatments such as bisoprolol 10 mg, metoprolol 200 mg, propranolol 80 mg, or valproate 500 mg (1396,105480). These findings are limited due to small study size and a lack of power to detect a difference between groups. Limited research has also evaluated riboflavin in children. A network meta-analysis of 3 small clinical trials in children with migraine shows that taking oral riboflavin 100-200 mg daily for 4-12 months does not significantly reduce incidence of migraine when compared with placebo. However, there was a non-significant trend towards reduced migraine frequency. Furthermore, conventional treatments such as propranolol, pregabalin, valproate, and topiramate were not shown to be significantly better than riboflavin for migraine prevention (105484). These findings are limited by small population sizes and insufficient power to detect differences between groups. Although riboflavin 100-200 mg has been used in prospective clinical studies, small observational studies have found some benefit in children taking riboflavin doses as low as 10-40 mg daily and as high as 400 mg daily for 3-4 months (105481,105485). Riboflavin has also been studied in combination with other ingredients, with research suggesting potential benefit. Specifically, riboflavin 400 mg has been combined with magnesium 600 mg and coenzyme Q10 150 mg daily (Dolovent; Linpharma Inc.) (92101), and also with magnesium 300 mg and feverfew 100 mg daily (12389).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using oral riboflavin for acne, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Alzheimer disease. Although there is interest in using oral riboflavin for Alzheimer disease, there is insufficient reliable information about the clinical effects of riboflavin for this condition.
• Cardiovascular disease (CVD). It is unclear if oral riboflavin can prevent mortality due to CVD. Details: Epidemiological research has found that dietary and supplemental riboflavin intake in the highest quartile, around 3.4 mg daily, is associated with a 47% lower risk of CVD mortality when compared with riboflavin intake in the lowest quartile, around 1 mg/day. The reduction in CVD mortality with riboflavin was enhanced by higher folate intake (110727). The validity of this finding is limited by the fact that dietary riboflavin intake was based on 2-day dietary recall.
• Carpal tunnel syndrome. Although there is interest in using oral riboflavin for carpal tunnel syndrome, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Cataracts. It is unclear if oral riboflavin is beneficial in patients with cataracts. Details: Observational research has found that high dietary intake of riboflavin is associated with a reduced risk of nuclear cataracts and age-related lens opacification (6378,14301). Furthermore, a clinical study in Chinese patients with nutrient deficiencies shows that taking a combination of riboflavin 3 mg plus niacin 40 mg daily also seems to reduce the risk of developing nuclear cataracts when compared with no supplementation (4885). It is unclear if the benefit is due to riboflavin, niacin, or the combination.
• Cervical cancer. It is unclear if oral riboflavin helps to prevent cervical cancer. Details: Epidemiological evidence has found that increased riboflavin intake from dietary and supplement sources, along with other B vitamins, is associated with a reduced risk of precancerous cervical lesions (11074).
• Colorectal cancer. It is unclear if oral riboflavin reduces colorectal cancer risk. Details: Epidemiological evidence in a Chinese population has found that increased dietary intake of riboflavin is associated with a reduced risk of developing colorectal cancer (105482).
• Diabetic neuropathy. Intravenous and oral riboflavin have only been evaluated in combination with other ingredients; riboflavin's effect when used alone is unclear. Details: Clinical research in patients with type 2 diabetes shows that intravenous administration of a specific combination product containing succinic acid, inosine, nicotinamide, and riboflavin (Cytoflavin, Polysan) daily for 10 days followed by an oral formulation of the same product, taken daily for 76 days, reduces symptoms of diabetic neuropathy including paresthesia, numbness, and burning when compared with placebo (110503). It is unclear if these findings are due to riboflavin, other ingredients, or the combination.
• Esophageal cancer. It is unclear if oral riboflavin reduces esophageal cancer risk. Details: Population research in Iranian patients has found that low riboflavin status is associated with a two-fold increase in the risk of esophageal cancer (71439). However, not all evidence agrees. Preliminary clinical studies in Chinese individuals with esophageal dysplasia shows that taking riboflavin, alone or in combination with calcium or niacin, for 3-5 years does not seem to reduce the risk of esophageal cancer in patients when compared with baseline or control (4679,63576,71488). Taking riboflavin 200 mg weekly, in combination with retinol 15 mg and zinc 50 mg, also does not seem to be beneficial in this patient population (71501). It is unclear if these findings are generalizable to geographic locations other than China and Iran.
• Gastric cancer. It is unclear if oral riboflavin reduces colorectal cancer risk. Details: Low quality clinical research in a Chinese population shows that taking riboflavin in combination with niacin does not appear to reduce the risk of gastric cancer when compared with control (4679).
• Hypertension. There is limited evidence on the oral use of riboflavin for reducing blood pressure in patients with the MTHFR 677 TT genotype. Details: A 677 C to T polymorphism on the MTHFR gene has been associated with hypertension. In patients with a confirmed MTHFR 677 TT genotype and premature cardiovascular disease, preliminary clinical research suggests that taking riboflavin 1.6 mg daily for 16 weeks reduces systolic blood pressure (SBP) by 9 mmHg and diastolic blood pressure (DBP) by 6 mmHg when compared with placebo . This decrease in blood pressure is larger than that reported in other trials, which may be due to the fact that only patients with the 677 TT genotype were included. These patients seem to respond to riboflavin therapy more so than patients with 677 CC or 677 CT genotype (92102). Additional clinical research in patients with the 677 TT genotype but without cardiovascular disease shows that taking riboflavin 1.6 mg daily for 16 weeks reduces SBP by 5.6 mmHg but does not reduce DBP (92103). There is also interest in using dietary riboflavin for reducing the onset of hypertension. Some epidemiological evidence in a Chinese population has found that increased dietary intake of riboflavin is associated with a reduced risk of developing hypertension (105483).
• Liver cancer. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals older than 55 years shows that taking riboflavin in combination with niacin does not seem to prevent liver cancer mortality when compared with control. However, there was a reduced risk of liver cancer mortality in people aged less than 55 years when compared with control (63470).
• Lung cancer. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals shows that taking riboflavin in combination with niacin does not appear to reduce the risk of lung cancer when compared with control (34539).
• Malaria. Oral riboflavin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children ages 5-14 years living in Gambia and at high risk for malaria exposure suggests that taking riboflavin, in combination with iron, thiamine, and vitamin C, for 3 months does not reduce the frequency or severity of malaria infections when compared with placebo (56730).
• Malnutrition. There is limited evidence on the oral use of riboflavin with other ingredients in children at risk for kwashiorkor. Details: A clinical study in Malawian children at risk for kwashiorkor, a severe form of malnutrition, suggests that taking riboflavin, vitamin E, selenium, and N-acetyl cysteine at a dose of three times the recommended dietary allowance does not prevent kwashiorkor, reduce edema, increase physical growth, or reduce infection when compared with placebo (71433).
• Mitochondrial myopathies. Although there is interest in using oral riboflavin for mitochondrial myopathies, there is insufficient reliable information about the clinical effects of riboflavin for this condition.
• Multiple sclerosis (MS). It is unclear if oral riboflavin slows the progression of MS-related disability. Details: A small clinical study in patients with relapsing-remitting MS or secondary progressive MS who are undergoing treatment with disease-modifying therapies suggests that taking oral riboflavin 10 mg daily for six months is no more effective for improving disability than placebo (91752). The validity of this finding is limited by the small study sample size.
• Oral leukoplakia. It is unclear if oral riboflavin prevents or slows progression of oral leukoplakia. Details: Population research in people living in Uzbekistan has found that low blood levels of riboflavin are associated with an increased prevalence of oral leukoplakia (71502). However, clinical evidence in patients with a high occurrence of oral and esophageal cancer who are living in Uzbekistan suggests that taking riboflavin 80 mg weekly for 20 months does not improve the prevalence or progression of oral leukoplakia when compared to baseline (71565). The validity of this finding is limited by the lack of a placebo group and unusual once weekly dosing. Furthermore, it is unclear if these results are generalizable to other geographic locations.
• Pre-eclampsia. Although there is interest in using oral riboflavin for pre-eclampsia, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Pregnancy-related iron deficiency. It is unclear if oral riboflavin is beneficial in patients with iron deficiency due to pregnancy. Details: Preliminary clinical research in pregnant patients in China suggests that adding riboflavin 1 mg daily to supplemental iron and folic acid does not improve iron status when compared with taking iron and folic acid alone (71480).
• Sickle cell disease. It is unclear if oral riboflavin is beneficial in patients with sickle cell disease. Details: One small clinical study in patients with sickle cell disease suggests that taking riboflavin 5 mg twice daily for 8 weeks increases serum iron and transferrin saturation when compared to baseline; however, riboflavin does not seem to improve serum ferritin or circulating hemoglobin levels (71566).
• Stroke. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals with poor nutritional status who are at risk for stroke suggests that taking riboflavin 5.2 mg daily in combination with niacin 40 mg daily does not reduce the risk of stroke-related mortality (2673). More evidence is needed to rate riboflavin for these uses.

(Read more about RIBOFLAVIN)

LIKELY SAFE . .when used orally and appropriately. Cranberry juice up to 300 mL daily and cranberry extracts in doses up to 800 mg twice daily have been safely used in clinical trials (3333,3334,6758,6760,7008,8252,8253,8254,8995,11328) (16415,16720,17100,17126,17176,17210,17524,46379,46388,46389)(46390,46425,46439,46443,46465,46456,46466,46467,46469,46471)(46496,46499,90044,102847,111407).

CHILDREN: LIKELY SAFE
when cranberry juice is consumed in amounts commonly found in the diet (2811,6759,46441,46452,46470,111407). There is insufficient reliable information available about the safety of cranberry when used in medicinal amounts in children.

PREGNANCY AND LACTATION: LIKELY SAFE
when consumed in amounts commonly found in the diet. There is insufficient reliable information available about the safety of cranberry when used therapeutically during pregnancy or lactation; avoid using.

(Read more about CRANBERRY)

LIKELY SAFE ...when olive fruit is used orally and appropriately in amounts commonly found in foods.

POSSIBLY SAFE ...when olive leaf extract is used orally and appropriately. Olive leaf extract providing 51-100 mg oleuropein daily has been used with apparent safety for 6-8 weeks (92245,92247,101860). There is insufficient reliable information available about the safety of olive fruit extract when used in amounts greater than those found in foods.

PREGNANCY AND LACTATION:
Insufficient reliable information available; stick with amounts commonly found in foods.

(Read more about OLIVE)

POSSIBLY SAFE ...when perilla oil or extract is used orally and appropriately. There is some evidence that perilla can be safely used for up to 12 months (1338,68676,94312,105525).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about PERILLA)

LIKELY SAFE ...when used orally and appropriately in medicinal amounts. Policosanol seems to be safe when used in doses of 5-80 mg daily for up to 3 years (2927,2928,2929,2930,2931,2943,2944,12166,14298,14336)(14404,14411,65383,89438,89454,89451,100178,103832).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about POLICOSANOL)

LIKELY SAFE ...when used orally and appropriately. Riboflavin 400 mg daily has been taken for up to 3 months, and 10 mg daily has been taken safely for up to 6 months (4912,91752,105480). A tolerable upper intake level (UL) has not been established (3094,91752,94089).

CHILDREN: LIKELY SAFE
when used orally and appropriately in dietary amounts. A tolerable upper intake level (UL) has not been established (3094,94089). ...when used orally in higher doses for up to 1 year. Doses of 100-200 mg daily have been used safely for 4-12 months in children ages 9-13 years (71483,105484).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately in dietary amounts. A tolerable upper intake level (UL) has not been established (3094,94089).

(Read more about RIBOFLAVIN)

ATORVASTATIN (Lipitor) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cranberry might increase levels and adverse effects of atorvastatin.  Details In one case report, a patient taking atorvastatin experienced upper back pain, rhabdomyolysis, and abnormal liver function after drinking cranberry juice 16 ounces daily for 2 weeks. Theoretically, this may have been caused by inhibition of cytochrome P450 3A4 (CYP3A4) enzymes by cranberry juice, as atorvastatin is a CYP3A4 substrate. Creatinine kinase and liver enzymes normalized within 2 weeks of stopping cranberry juice (90042). Patients taking atorvastatin should avoid large quantities of cranberry juice.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, cranberry might increase the levels and adverse effects of CYP2C9 substrates. However, research is conflicting.  Details There is contradictory evidence about the effect of cranberry on CYP2C9 enzymes. In vitro evidence suggests that flavonoids in cranberry inhibit CYP2C9 enzymes (10452,11115,90048). However, clinical research shows that cranberry juice does not significantly affect the levels, metabolism, or elimination of the CYP2C9 substrates flurbiprofen or diclofenac (11094,90048). Also, in patients stabilized on warfarin, drinking cranberry juice 250 mL daily for 7 days does not significantly increase the anticoagulant activity of warfarin, a CYP2C9 substrate (15374). Additional pharmacokinetic research shows that cranberry juice does not increase peak plasma concentrations or area under the concentration-time curve of warfarin (15393).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cranberry might increase the levels and adverse effects of CYP3A4 substrates.  Details A case of upper back pain, rhabdomyolysis, and abnormal liver function has been reported for a patient taking atorvastatin, a CYP3A4 substrate, in combination with cranberry juice 16 ounces daily for 2 weeks. Creatinine kinase and liver enzymes normalized within 2 weeks of stopping cranberry juice (90042). Also, animal research suggests that cranberry juice, administered intraduodenally 30 minutes prior to nifedipine, a CYP3A4 substrate, inhibits nifedipine metabolism and increases the area under the concentration-time curve by 1.6-fold compared to control (46420).

DICLOFENAC (Voltaren, others) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, cranberry might modestly increase the levels and adverse effects of diclofenac.  Details In vitro evidence suggests that cranberry juice inhibits diclofenac metabolism by human liver microsomes (90048). However, drinking cranberry juice does not seem to affect diclofenac metabolism in humans (90048).

NIFEDIPINE (Procardia) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cranberry might increase the levels and adverse effects of nifedipine.  Details Animal research suggests that cranberry juice, administered intraduodenally 30 minutes prior to nifedipine treatment, inhibits nifedipine metabolism and increases the area under the concentration-time curve by 1.6-fold compared to control (46420). This interaction has not been reported in humans.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, cranberry might increase the levels and adverse effects of warfarin. However, research is conflicting.  Details There is contradictory evidence about the effect of cranberry juice on warfarin. Case reports have linked cranberry juice consumption to increases in the international normalized ratio (INR) in patients taking warfarin, resulting in severe spontaneous bleeding and excessive postoperative bleeding (10452,12189,12668,21187,21188,21189,46378,46396,46411)(46415,90043). Daily consumption of cranberry sauce for one week has also been linked to an increase in INR in one case report (16816). In a small study in healthy young males, taking a high dose of 3 grams of cranberry juice concentrate capsules, equivalent to 57 grams of fruit daily, for 2 weeks produced a 30% increase in the area under the INR-time curve after a single 25-mg dose of warfarin (16416). However, 3 very small clinical studies in patients stabilized on warfarin reported that cranberry juice 250 mL once or twice daily for 7 days (27% cranberry juice or pure cranberry juice) or 240 mL once daily for 14 days does not significantly increase INR or affect plasma warfarin levels (15374,17124,90045). The reasons for these discrepant findings are unclear. It is possible that the form and dose of cranberry may play a role, as cranberry extracts and juices contain different constituents. Additionally, an in vitro study evaluating 5 different cranberry juices found varying effects, with only a cranberry concentrate, and not diluted cranberry juices, inhibiting CYP2C9. However, this concentrate did not inhibit CYP2C9 activity in humans (108062).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking policosanol with other antiplatelet or anticoagulant drugs might increase the risk of bruising and bleeding.  Details Some clinical research shows that taking policosanol 10-50 mg daily for 7-15 days can inhibit platelet aggregation in healthy patients (2936,2937,2938,103832). Although, one clinical trial shows that taking policosanol 10 mg twice daily for 2 weeks prior to warfarin dosing does not affect warfarin pharmacokinetics or warfarin response (20083). Furthermore, a study in patients undergoing percutaneous coronary intervention with a drug-eluting stent found that taking policosanol 40 mg plus clopidogrel and aspirin daily for 30 days modestly reduced the risk for minor bleeding events when compared with taking clopidogrel and aspirin alone (100684). Until more is known, use with caution.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, policosanol might have additive effects with antidiabetes drugs and increase the risk of hypoglycemia.  Details Clinical research shows that policosanol can lower blood glucose levels (100178).

BETA-BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Concomitant use of policosanol with beta-blockers can cause additive blood pressure-lowering effects.  Details Clinical research shows that policosanol 5 mg daily can have additive blood pressure-lowering effects in patients with hypertension who are taking beta-blockers (65383). Also, animal research shows that policosanol can increase the blood-pressure lowering effects of propranolol (23775).

NITROPRUSSIDE (Nitropress) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of policosanol with nitroprusside might cause additive blood pressure-lowering effects.  Details Animal research shows that taking policosanol along with nitroprusside can increase the blood pressure-lowering effects of nitroprusside (65374).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking policosanol with warfarin might increase the risk of bruising and bleeding.  Details Some clinical research shows that taking policosanol 10-50 mg daily for 7-15 days can inhibit platelet aggregation in healthy patients (2936,2937,2938). However, one clinical trial shows that taking policosanol 10 mg twice daily for 2 weeks prior to warfarin dosing does not affect warfarin pharmacokinetics or warfarin response (20083).

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TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking riboflavin with tetracycline antibiotics may decrease the potency of these antibiotics.  Details In vitro research suggests that riboflavin may inhibit the potency of tetracycline antibiotics (23372). It is not clear if this effect is clinically significant, as this interaction has not been reported in humans.

(Read more about RIBOFLAVIN)

General ...Orally, cranberry seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea and gastrointestinal discomfort.

Dermatologic ...Orally, skin redness and itching has been reported in one patient (46389).

Gastrointestinal ...In very large doses, for example 3-4 L per day of juice, cranberry can cause gastrointestinal upset and diarrhea, particularly in young children (46364). There are reports of abdominal and gastrointestinal discomfort after taking cranberry tablets, extracts, and juice in clinical trials (16720,46379,111407). Nausea, vomiting, and diarrhea have also been reported with consumption of lower doses of cranberry juice cocktail, 16 ounces per day, equivalent to about 4 ounces cranberry juice, for several weeks (16415).

Genitourinary ...Vulvovaginal candidiasis has been associated with ingestion of cranberry juice (46374). Clinical research suggests that ingestion of cranberry juice may be associated with vaginal itching and vaginal dryness (46471). One patient in clinical research stopped taking dried cranberry juice due to excessive urination (46437), and an isolated case of nocturia following ingestion of cranberry tablets has been reported (16720).

Hematologic ...Thrombocytopenia has been reported as an adverse event to cranberry juice (46459).

Other ...An isolated case of sensitive swollen nipples after taking cranberry tablets has been reported (16720).

(Read more about CRANBERRY)

General ...Orally, olive fruit is well tolerated when used in typical food amounts. Olive leaf extract seems to be well tolerated.
Most Common Adverse Effects:
Orally: Headache and stomach discomfort.

Dermatologic ...Orally, one patient in one clinical trial reported bad skin and acne after using olive leaf extract (101860).

Gastrointestinal ...Orally, three patients in one clinical trial reported stomach ache after using olive leaf extract (101860).

Neurologic/CNS ...Orally, three patients in one clinical trial reported headache after using olive leaf extract (101860).

Psychiatric ...In one case report, a 67-year-old female experienced irritability, anger, a lack of control, and feelings of sadness and negativity after consuming a multi-ingredient product containing olive leaf extract 5 grams, horseradish root, and eyebright daily for 38 days. All psychiatric symptoms disappeared within days of stopping the combined product. It is hypothesized that the hydroxytyrosol component of olive leaf extract contributed to these symptoms due to its chemical similarity to dopamine; however, it is not clear if these symptoms were due to the olive leaf extract or to the other ingredients (96245).

Pulmonary/Respiratory ...Olive tree pollen can cause seasonal respiratory allergy (1543).

(Read more about OLIVE)

General ...Orally, perilla seems to be well tolerated. Topically, there is currently a limited amount of information on the adverse effects of perilla.
Most Common Adverse Effects:
Topically: Dermatitis.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis.

Dermatologic ...Topically, perilla may cause contact dermatitis (6,68664,94313).

Immunologic ...Orally, many cases of anaphylaxis have been reported in adults and children who consumed perilla seeds (94313,110611). Some research suggests that oleosin is the major constituent responsible for perilla allergies (110611).

Pulmonary/Respiratory ...Occupational asthma has been reported from breathing in smoke from roasted perilla seeds (94313).

(Read more about PERILLA)

General ...Orally, policosanol is usually well-tolerated.
Most Common Adverse Effects:
Orally: Dysuria, headache, insomnia, polyphagia, pruritis, skin rash, somnolence, upset stomach, vertigo, weight loss.

Dermatologic ...Orally, policosanol can cause pruritus or skin rash, but these events appear to be uncommon (65369,95374,100178). In one clinical trial that included over 50 patients, one case of policosanol-associated skin rash was reported (65369). In another study, 1 out of 40 patients treated with policosanol 10 mg daily reported pruritus (95374).

Gastrointestinal ...Orally, policosanol can cause upset stomach or polyphagia (2937).

Genitourinary ...Orally, policosanol can cause dysuria (2937).

Hematologic ...A case gum bleeding has been reported in a patient taking policosanol 20 mg and aspirin 100 mg daily for 7 days (2937).

Neurologic/CNS ...Orally, policosanol may cause headache, mild vertigo, somnolence, irritability, or insomnia but these events are uncommon. In one clinical study, 1 out of 44 subjects receiving policosanol 20 mg daily 12 weeks experienced mild vertigo and 2 out of 44 experienced mild headache (14404). In another study, 2 out of 70 patients taking policosanol 10 mg daily for 8 weeks experienced headache (69119). In another study, 1 out of 40 patients taking policosanol 10 mg daily reported insomnia (95374).

Other ...Orally, policosanol has been associated with weight loss. However, evidence from a post-market surveillance study of patients taking policosanol 5-15 mg daily shows that this adverse event is uncommon (95375).

(Read more about POLICOSANOL)

General ...Orally, riboflavin is generally well tolerated.
Most Common Adverse Effects:
Orally: Dose-related nausea and urine discoloration.

Gastrointestinal ...Orally, riboflavin has been associated with rare diarrhea and dose-related nausea (1398,71483). In one clinical study, one subject out of 28 reported having diarrhea two weeks after starting riboflavin 400 mg daily (1398).

Genitourinary ...Orally, high doses of riboflavin can cause bright yellow urine. Furthermore, in one clinical study, one subject out of 28 reported polyuria two weeks after starting riboflavin 400 mg daily (1398,3094).

(Read more about RIBOFLAVIN)