Miracle Reds Fresh Berri Berri Bar by MacroLife Naturals

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Androgenic alopecia. Although there has been interest in using topical agave for androgenic alopecia, there is insufficient reliable information about the clinical effects of agave for this purpose.
• Bruises. Although there has been interest in using topical agave for bruises, there is insufficient reliable information about the clinical effects of agave for this purpose.
• Cancer. Although there has been interest in using oral agave for cancer, there is insufficient reliable information about the clinical effects of agave for this purpose.
• Constipation. Although there has been interest in using oral agave for cancer, there is insufficient reliable information about the clinical effects of agave for this purpose.
• Diarrhea. Although there has been interest in using oral agave for diarrhea, there is insufficient reliable information about the clinical effects of agave for this purpose.
• Dyspepsia. Although there has been interest in using oral agave for dyspepsia, there is insufficient reliable information about the clinical effects of agave for this purpose.
• Flatulence. Although there has been interest in using oral agave for flatulence, there is insufficient reliable information about the clinical effects of agave for this purpose.
• Lactation. Although there has been interest in using oral agave for lactation, there is insufficient reliable information about the clinical effects of agave for this purpose.
• Liver disease. Although there has been interest in using oral agave for liver disease, there is insufficient reliable information about the clinical effects of agave for this purpose. More evidence is needed to rate agave for these uses.

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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.
• Periodontitis. Topical cranberry extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with chronic periodontitis shows that applying a topical combination gel product containing cranberry extract 2.5 grams and garcinia extract after scaling and root planing reduces plaque index, gingival index, probing pocket depth, clinical attachment level, and salivary biomarkers of periodontal disease when compared with scaling and root planing alone and similarly to scaling and root planing with tetracycline fibers (112272). It is unclear if these effects are due to cranberry, garcinia, or the combination.
• 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 oral cranberry 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). In contrast, another small study in adults with RA shows that drinking reduced-calorie cranberry juice 500 mL daily for 90 days does not improve disease activity score or clinically relevant biologic markers of RA such as rheumatoid factor, anti-cyclic citrullinated peptide antibodies, erythrocyte sedimentation rate, or C-reactive protein when compared with a control group (112273).
• 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.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. A small preliminary clinical study in females 46-58 years of age shows that applying a cream containing date palm kernel extract 5% around the eyes twice daily for 5 weeks might reduce skin wrinkles. Applying the cream reduced the surface area of wrinkles by 28% and the depth of wrinkles by 3.5% and also improved the subjective appearance of wrinkles in 60% of the patients (47093).
• Male infertility. Preliminary clinical research shows that taking date palm pollen powder 120 mg/kg every other day for 2 months improves sperm count by 52% and sperm motility by 27% when compared with baseline in infertile males. However, these measures did not reach normal values (98655). The validity of this finding is limited by the lack of a comparator group.
• Neutropenic fever. Preliminary clinical research in children (mean age of about 9 years) with various types of cancer shows that eating 3-5 Ajwa date palm fruits (average intake 7 grams) with breakfast daily throughout cancer treatment reduces hospital admissions for neutropenic fever and infections, and is associated with a better survival rate, when compared with patients not eating date palm fruit (106734). The validity of these results is limited by the lack of randomization, dose standardization, or blinding, and the variability in types of tumor and stage.
• Oral mucositis. Preliminary clinical research in patients receiving radiation and chemotherapy for head and neck cancer shows that swishing and swallowing a solution containing date palm pollen at bedtime for 6 weeks prevents the development of oral mucositis when compared with standard care with an antifungal agent and analgesics. Only 10% of patients using the date palm pollen solution required soft or liquid food compared with 80% of patients receiving standard care (98654).
• Parturition. A meta-analysis of 6 low- to medium-quality studies in patients at 36-42 weeks of gestation shows that eating date palm fruit during labor reduces the duration of the active phase of labor and improves cervical readiness (Bishop score). However, there is no effect on the duration of the first, second, or third stages of labor, or the frequency of Caesarian sections (106430).
• Pre-eclampsia. Preliminary clinical research in pregnant patients, with a mean gestational age of about 22 weeks and at least one risk factor for pre-eclampsia, shows that eating seven Ajwa date palm fruits daily for 8 weeks reduces mean arterial pressure by 13%, compared with an increase of 8% in patients not eating date palm fruit. Blood pressure in the roll-over test is reduced by 66% in patients consuming date palm fruit, compared with an increase of 6% in those not doing so (106735). These results suggest a reduction in the risk for pre-eclampsia, but data on the incidence of the condition in either group is not provided. More evidence is needed to rate date palm for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Topical red raspberry leaf has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in females aged 30-65 years shows that applying a specific liquid (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) containing red raspberry leaf cell culture extract 0.0005%, vitamin C 20%, and vitamin E 1% to the face nightly for 8 weeks, in addition to regular facial skin products, improves skin color, elasticity, radiance, smoothness, and appearance of wrinkles when compared with regular facial skin products alone (102355).
• Cardiovascular disease (CVD). Although there has been interest in using oral red raspberry leaf for CVD, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Congestive heart failure (CHF). Although there has been interest in using oral red raspberry leaf for CHF, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Diabetes. Although there has been interest in using oral red raspberry leaf for diabetes, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Dysmenorrhea. Although there has been interest in using oral red raspberry leaf for dysmenorrhea, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Hypertension. Although there has been interest in using oral red raspberry leaf for hypertension, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Influenza. Although there has been interest in using oral red raspberry leaf for influenza, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Labor pain. Some research suggests that oral red raspberry leaf does not reduce analgesic use during labor. Details: Clinical research shows that taking red raspberry leaf 2.4 grams daily, beginning at 32 weeks' gestation and continuing until delivery, does not decrease the need for analgesics in the perinatal time period when compared with placebo (9796). A systematic review of retrospective studies also supports these findings, showing no improvement in perineal outcomes in patients consuming red raspberry leaf prior to labor (108005).
• Menorrhagia. Although there has been interest in using oral red raspberry leaf for menorrhagia, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Obesity. It is unclear if oral red raspberry fruit is beneficial in patients with obesity. Details: Preliminary clinical research in overweight and obese adults shows that consuming frozen red raspberry fruit 280 grams daily for 8 weeks does not reduce body mass index or waist circumference when compared with control (105873).
• Osteoarthritis. It is unclear if oral red raspberry leaf extract is beneficial for knee osteoarthritis. Details: A moderate-sized clinical study in patients with knee osteoarthritis shows that taking red raspberry leaf extract 200 or 400 mg once daily for 12 weeks reduces pain at the higher dose when measured by the visual analog scale, but does not improve physical performance, physical activity, walking distance, or Western Ontario McMaster osteoarthritis index (WOMAC) global score or pain, stiffness, and function subscores when compared with placebo (112127).
• Parturition. Some research suggests that oral red raspberry leaf does not shorten the duration of labor. Details: Clinical research shows that taking red raspberry leaf 2.4 grams daily, beginning at 32 weeks' gestation and continuing until delivery, does not reduce the length of labor when compared with placebo (108005). Traditionally, doses of up to 4 grams daily have been recommended for this purpose; however, doses greater than 2.4 grams daily have not been evaluated for safety or efficacy. Further high-quality research is needed to determine the optimal dose, duration, and formulation, if any, of red raspberry leaf for this purpose.
• Pharyngitis. Although there has been interest in using topical red raspberry leaf for pharyngitis, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Pregnancy-induced nausea and vomiting. Although there has been interest in using oral red raspberry leaf for pregnancy-induced nausea and vomiting, there is insufficient reliable information about the clinical effects of red raspberry for this purpose.
• Respiratory tract infections. Although there has been interest in using oral red raspberry leaf for respiratory tract infections, there is insufficient reliable information about the clinical effects of red raspberry for this purpose. More evidence is needed to rate red raspberry leaf for this use.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cardiovascular disease (CVD). Pooled analyses of clinical research show that taking freeze-dried strawberry powder or eating fresh strawberries for 3-12 weeks can reduce levels of C-reactive protein, a marker of inflammation and risk factor for CVD, by 0.47-0.63 mg/L when compared with placebo. These analyses report conflicting effects on blood pressure and lipid levels (103881,103882), with one analysis reporting small improvements that are not clinically significant (103881). It is unclear whether strawberry can prevent CVD or related outcomes.
• Diabetes. Preliminary clinical research in adults with type 2 diabetes shows that taking freeze-dried strawberry powder 50 grams daily for 6 weeks reduces glycated hemoglobin (HbA1c) by 0.47% compared to an increase of 0.15% with placebo. However, there were no changes in serum glucose, anthropometric measurements, blood lipids, or blood pressure. Also, the short duration of supplementation makes it unclear whether the change in HbA1c was due to strawberry (100113,100119).
• Hyperlipidemia. Data on the effects of strawberry on serum lipids are conflicting. Clinical research in adults with abdominal obesity and elevated serum lipids shows that taking freeze-dried strawberry powder 50 grams daily for 12 weeks reduces total and low-density lipoprotein (LDL) cholesterol when compared with either placebo or taking 25 grams of freeze-dried strawberry daily. In those taking 50 grams daily, levels of LDL cholesterol decreased by approximately 21% from baseline, compared with a 2% reduction in those taking placebo. However, strawberry did not improve levels of high-density lipoprotein (HDL) cholesterol or triglycerides (100109). Another study also reported reduced levels of total and LDL cholesterol (112318), while others report no changes in any lipid levels (112320,112321). In a meta-analysis, strawberry was associated with mean decreases of 11 mg/dL in LDL levels, and 12 mg/dL in total cholesterol, as well as increases in high-density lipoprotein (HDL) cholesterol (112323).
• Hypertension. Preliminary clinical research in postmenopausal women with pre- or stage I hypertension shows that taking freeze-dried strawberry powder 25 or 50 grams daily for 8 weeks does not reduce blood pressure when compared with placebo. However, over 50% of the included women were also taking at least one blood pressure lowering medication (100111).
• Obesity. Clinical research in adults with obesity or abdominal obesity and elevated serum lipids shows that taking freeze-dried strawberry powder 50 grams daily for 12 weeks does not reduce body weight or adiposity when compared with either placebo or freeze-dried strawberries 25 grams daily (100109,100116). Similarly, preliminary clinical research in adults with type 2 diabetes who are overweight or obese shows that taking freeze-dried strawberry powder 50 grams daily for 6 weeks does not improve weight loss when compared with placebo (100113). Evidence from mainly small, lower-quality studies is mixed as to whether taking strawberries has beneficial effects on cardiovascular risk factors when compared to control in obese individuals (100109,100116,100118).
• Osteoarthritis. Preliminary clinical research in obese adults with osteoarthritis shows that taking freeze-dried strawberry powder 50 grams daily for 12 weeks reduces some, but not all, measures of pain by up to 45%, compared to no change in those taking placebo (100116). More evidence is needed to rate strawberry for these uses.

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POSSIBLY UNSAFE ...when fresh agave is used topically. Exposure to agave can cause localized swelling and redness, the formation of red, purple, or black skin lesions, and inflammation of small blood vessels (leukocytoclastic vasculitis) within minutes to hours of exposure (26144,26145). The most irritating portion of the plant appears to be the sap, although irritants may also be present in the leaves, stem, flowers, roots, and bulbs (26144). There is insufficient reliable information available about the safety of agave when used orally.

PREGNANCY: LIKELY UNSAFE
when used orally. Agave contains constituents that may be uterine stimulants, and it has traditionally been used to induce labor (20017).

LACTATION:
Insufficient reliable information available; avoid using.

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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.

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LIKELY SAFE ...when date palm fruit is used orally in amounts commonly found in foods.

POSSIBLY SAFE ...when date palm pollen is used orally and appropriately, short-term. Date palm pollen powder has been used with apparent safety at a dose of 120 mg/kg every other day for up to 2 months or at a dose of 2 grams daily for up to 6 weeks (98654,98655). There is insufficient reliable information available about the safety of date palm fruit in medicinal amounts.

PREGNANCY AND LACTATION:
Insufficient reliable information; avoid using in amounts greater than those commonly found in foods.

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LIKELY SAFE ...when the fruit is used orally in amounts commonly found in foods (13622).

POSSIBLY SAFE ...when the fruit is used orally and appropriately in medicinal amounts (6481,9796). There is insufficient reliable information available about the safety of red raspberry leaf when used orally or topically.

PREGNANCY: LIKELY SAFE
when the fruit is used orally in amounts commonly found in foods (13622).

PREGNANCY: POSSIBLY SAFE
when red raspberry leaf is used orally and appropriately in medicinal amounts during late pregnancy under the supervision of a healthcare provider. Red raspberry leaf is used by nurse midwives to facilitate delivery. There is some evidence that red raspberry leaf in doses of up to 2.4 grams daily, beginning at 32 weeks' gestation and continued until delivery, can be safely used for this purpose (6481,9796). Make sure patients do not use red raspberry leaf without the guidance of a healthcare professional.

PREGNANCY: LIKELY UNSAFE
when red raspberry leaf is used orally in medicinal amounts throughout pregnancy or for self-treatment. Red raspberry leaf might have estrogenic effects (6180). These effects can adversely affect pregnancy. Tell pregnant patients not to use red raspberry leaf at any time during pregnancy without the close supervision of a healthcare provider.

LACTATION: LIKELY SAFE
when the fruit is used orally in amounts commonly found in foods (13622). There is insufficient reliable information available about the safety of red raspberry leaf; avoid using.

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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 = D Theoretically, taking red raspberry leaf with anticoagulant/antiplatelet drugs might increase the risk of bleeding.  Details In vitro research suggests that red raspberry leaf extract has antiplatelet activity and enhances the in vitro effects of the antiplatelet medication cangrelor (96300). This interaction has not been reported in humans.

INSULIN Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Red raspberry leaf might reduce glucose levels in patients being treated with insulin.  Details In one case report, a 38-year-old patient with gestational diabetes, whose blood glucose was being controlled with medical nutrition therapy and insulin, developed hypoglycemia after consuming two servings of raspberry leaf tea daily for 3 days beginning at 32 weeks' gestation. The patient required an insulin dose reduction. The hypoglycemia was considered to be probably related to use of red raspberry leaf tea (96299).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D In vitro and animal research suggests that strawberry extract can inhibit platelet aggregation due to its phenolic content (76472,76488). Theoretically, strawberry might increase the risk of bleeding when used with antiplatelet or anticoagulant drugs.  Details Some anticoagulant or antiplatelet drugs include aspirin, clopidogrel (Plavix), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, ticlopidine (Ticlid), warfarin (Coumadin), and others.

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D In vitro research suggests that strawberry extract can inhibit p-glycoprotein efflux (76474,76476). Theoretically, strawberry might inhibit p-glycoprotein mediated drug efflux and potentially increase levels of drugs that are substrates of p-glycoprotein. Until more is known, strawberry should be used cautiously in people taking p-glycoprotein substrates.  Details Drugs that might be affected include some chemotherapeutic agents (etoposide, paclitaxel, vinblastine, vincristine, vindesine), antifungals (ketoconazole, itraconazole), protease inhibitors (amprenavir, indinavir, nelfinavir, saquinavir), H2 antagonists (cimetidine, ranitidine), some calcium channel blockers (diltiazem, verapamil), corticosteroids, erythromycin, cisapride (Propulsid), fexofenadine (Allegra), cyclosporine, loperamide (Imodium), quinidine, and others.

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General ...Topically, agave may be unsafe. There is currently a limited amount of information on the adverse effects of oral agave. A thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Topically: Dermatitis.
Serious Adverse Effects (Rare):
Topically: Leukocytoclastic vasculitis.

Dermatologic ...There are reports of acute irritant contact dermatitis due to agave exposure, especially to the sap (19626,19627,26145,20014,20015). Oxalic acid crystals in the sap may be the cause of this irritation (20015). Treatment with oral antihistamines and topical saline compresses have been shown to reduce skin lesions following agave exposure within 7-10 days (19622,19623).

Gastrointestinal ...A case report describes a patient who developed a bezoar from eating agave (20021).

Other ...Exposure to agave can cause localized swelling and redness, the formation of red, purple, or black skin lesions, and inflammation of small blood vessels (leukocytoclastic vasculitis) within minutes to hours of exposure (26144,26145).

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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).

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General ...Orally, date palm fruit is safe when consumed as a food. It has been reported to cause allergic reactions (30204). Orally, date palm pollen appears to be generally well tolerated (98654,98655). When inhaled, allergy to date palm pollen is fairly common (30207,47102).

Immunologic ...By inhalation, date palm pollen has been reported to cause allergic rhinitis, wheezing, rhinoconjunctivitis, and bronchial asthma (30207,47102). Orally, date palm fruit has been reported to cause allergic reactions (30204).

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General ...Orally, red raspberry fruit is well tolerated. There is currently a limited amount of information on the adverse effects of red raspberry leaf.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal upset, and epigastric pain. However, these adverse effects do not commonly occur with typical doses.

Dermatologic ...A liquid containing red raspberry leaf cell culture extract 0. 0005%, vitamin C 20%, and vitamin E 1% (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) has been reported to cause mild tingling and skin tightness (102355). It is unclear if these effects are due to red raspberry leaf, the other ingredients, or the combination.

Gastrointestinal ...Orally, red raspberry may cause gastrointestinal upset, diarrhea, and epigastric pain (112127).

Pulmonary/Respiratory ...A case of occupational asthma due to the inhalation of red raspberry powder has been reported for a 35-year-old female. Symptoms included wheezing and shortness of breath (70370).

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General ...Orally, strawberry is well tolerated when taken in the amounts commonly found in food. When taken in medicinal amounts, strawberry seems to be generally well tolerated (100109,100113,100116,100119). Rarely, strawberry has been reported to cause nausea and allergic reactions, including oral allergy syndrome and skin reactions (100113,100119,103880).
Topically, strawberry can cause contact dermatitis (13637).

Gastrointestinal ...Orally, taking freeze-dried strawberry powder 50 grams daily has been reported to cause nausea in clinical trials (100113,100119).

Immunologic ...Orally, consuming strawberry has been reported to cause allergic reactions, including oral allergy syndrome and skin reactions, in some patients. (103880). Topically, strawberry has caused contact urticaria in one case report (13637). Overall, allergy to strawberry appears to be rare (103880).

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