Optimized Cran-Max [Discontinued] by Life Extension

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.

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POSSIBLY EFFECTIVE

• Hypertension. Oral Hibiscus sabdariffa seems to lower blood pressure by a small amount in patients with mild to moderate hypertension. Details: Most research shows that drinking Hibiscus sabdariffa tea daily can modestly lower blood pressure in patients with pre-hypertension or mild hypertension after 2-6 weeks of treatment (16894,54985,54995,90159,93817,101730,108867). In addition, some research shows that drinking Hibiscus sabdariffa tea daily can modestly lower blood pressure in patients with either untreated or insufficiently treated mild to moderate hypertension (54989,93815,101733,108867). These studies have used tea made from 1.25-10 grams or 150 mg/kg, brewed in 150 mL to 500 mL of water and taken one to three times daily for 2-6 weeks (16894,54985,54989,54995,90159,93815,93817,101730,101733,108867). The dose has been increased to 15 or 20 grams, brewed in 1000 mL for daily consumption for 2-3 weeks if needed (101733,108867). In this population, research shows that drinking Hibiscus sabdariffa tea or infusions is more effective than hydrochlorothiazide 25 mg daily and as effective as captopril 25 mg twice daily for lowering systolic and diastolic blood pressure (54989,93815). Pooled analyses of results from clinical research shows that drinking Hibiscus sabdariffa tea or taking Hibiscus sabdariffa extract lowers systolic blood pressure by 5-8 mmHg and diastolic blood pressure by about 4 mmHg in patients with or without mild hypertension (93817,105304). The clinical relevance of these results is uncertain due to the small size and low quality of the included studies. Some researchers suggest that there is insufficient reliable evidence to determine if the effects of Hibiscus sabdariffa are clinically relevant (17114). Taking Hibiscus sabdariffa in combination with other ingredients has also showed beneficial effects on blood pressure in clinical research. In one study, a specific product containing Hibiscus sabdariffa extract in combination with olive leaf extract (NW Roselle) for 8 weeks was found to be as effective as captopril 25 mg twice daily for reducing systolic and diastolic blood pressure (105302). In another study, a specific product (MetabolAid, Monteloeder S.L.) providing Hibiscus sabdariffa and lemon verbena extracts for 12 weeks reduced systolic, but not diastolic, blood pressure. However, these effects were limited to daytime ambulatory readings (105303).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cancer. Although there has been interest in using oral Hibiscus sabdariffa for cancer, there is insufficient reliable information about the clinical effects of Hibiscus sabdariffa for this condition.
• Constipation. Although there has been interest in using oral Hibiscus sabdariffa for constipation, there is insufficient reliable information about the clinical effects of Hibiscus sabdariffa for this purpose.
• Diabetes. It is unclear if oral Hibiscus sabdariffa is beneficial for diabetes. Details: Pooled analyses of results from clinical research show that taking Hibiscus sabdariffa lowers fasting blood glucose levels by approximately 4 mg/dL (105304,105305). However, only one low-quality study included in one of these analyses examined the effects of Hibiscus sabdariffa on fasting blood glucose levels in patients with type 2 diabetes (105305). Therefore, any benefit specific to this population is unclear.
• Dry mouth. Topical Hibiscus sabdariffa has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with dry mouth shows that taking a specific mucoadhesive tablet (Aqualief, Helsinn Healthcare SA), containing a combination of Hibiscus sabdariffa and carnosine, 400 mg three times daily after meals for 6 days increases saliva production and improves symptoms of dry mouth when compared to baseline. While saliva production was also increased in patients taking placebo, the increase was 3-fold greater with the combination product, and significant improvements in dry mouth symptoms were lacking in the placebo group (103288). It is unclear if these findings are due to Hibiscus sabdariffa, carnosine, or the combination.
• Dry skin. It is unclear if oral Hibiscus sabdariffa is beneficial for dry skin. Details: A crossover clinical study in healthy adults shows that drinking Hibiscus sabdariffa 100 mL twice daily for 6 months improves skin moisture but does not improve skin surface water loss or sebum secretion when compared to baseline (112426). However, it is unclear whether any improvements are clinically significant or apply to patients with dry skin.
• Dyslipidemia. It is unclear if oral Hibiscus sabdariffa is beneficial for dyslipidemia. Details: Some preliminary clinical research shows that drinking Hibiscus sabdariffa tea or taking Hibiscus sabdariffa extract can decrease total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, and can increase high-density lipoprotein (HDL) cholesterol, in patients with metabolic disorders (54997,54999). These studies used Hibiscus sabdariffa 2 grams in 240 mL boiling water, steeping for 20-30 minutes, twice daily and Hibiscus sabdariffa extract 100 mg daily, each for 4 weeks (54997,54999). Clinical research also shows that taking powdered dried Hibiscus sabdariffa 6 grams daily reduces LDL cholesterol by approximately 8% in obese adolescents with dyslipidemia (93816). Additionally, two meta-analyses shows that taking Hibiscus sabdariffa extract modestly reduces LDL cholesterol levels (105305,105306). However, other preliminary clinical research shows that taking Hibiscus sabdariffa extract does not improve cholesterol or triglyceride levels in patients with hypercholesterolemia (17415,55000). Two pooled analyses of clinical data show that Hibiscus sabdariffa does not improve total cholesterol, HDL cholesterol, LDL cholesterol, or triglycerides when compared with placebo, a change in diet, or black tea in patients with hyperlipidemia, metabolic disorders, or obesity (93805,105304). The differing conclusions of these trials and meta-analyses are related to their inclusion and exclusion criteria with respect to age and populations of focus.
• Kidney stones (nephrolithiasis). Although there has been interest in using oral Hibiscus sabdariffa for kidney stones, there is insufficient reliable information about the clinical effects of Hibiscus sabdariffa for this condition.
• Metabolic syndrome. Some small clinical studies suggest that oral Hibiscus sabdariffa may be beneficial for metabolic syndrome. Details: In adults with metabolic syndrome, a small clinical trial shows that taking Hibiscus sabdariffa powder 500 mg daily for 4 weeks modestly reduces systolic blood pressure and triglyceride levels by 5% and 15%, respectively, when compared with baseline. These changes were significant when compared with placebo. However, there was no effect on diastolic blood pressure, fasting glucose or insulin levels, cholesterol levels, or body mass index (105307). Other preliminary clinical research in adults with metabolic syndrome shows that taking Hibiscus sabdariffa extract 100 mg daily for one month modestly reduces fasting glucose and low-density lipoprotein (LDL) cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels when compared with baseline. When taken in combination with recommendations to follow the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) diet, triglyceride levels and blood pressure were also modestly reduced (54999).
• Obesity. Oral Hibiscus sabdariffa has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Two small clinical trials in overweight and obese females show that taking a combination product (MetabolAid, Monteloeder SL) containing Hibiscus sabdariffa and lemon verbena extracts as 500 mg per capsule daily for 2 months modestly increases weight loss when compared with placebo (97290,101731). This combination also reduces hunger and increases satiety, and has small to moderate beneficial effects on low-density lipoprotein (LDL) cholesterol, heart rate, and blood pressure (97290). The effects in obese individuals seem to be less than those seen in overweight individuals, with no overall change in abdominal circumference or percent body fat in obese individuals (101731). A meta-analysis of these two studies and several others in overweight or obese individuals shows that taking Hibiscus sabdariffa in combination with other ingredients daily for 6-12 weeks modestly improves body mass index, weight, and body fat percentage when compared with control (112427). However, the validity of these results is limited by the heterogeneity of the included studies. Additionally, it is unknown if these effects are due to Hibiscus sabdariffa, other ingredients, or the combination.
• Urinary tract infections (UTIs). It is unclear if oral Hibiscus sabdariffa is beneficial for UTIs. Details: Population research in patients with urinary catheters living in long-term care facilities has found that drinking Hibiscus sabdariffa tea is associated with a 36% lower risk of UTIs when compared with not drinking tea (93807). Some small clinical studies that have evaluated the use of Hibiscus sabdariffa in combination with other ingredients suggest that they might reduce the occurrence of symptomatic UTIs in females with recurrent UTIs. One study used a product containing Hibiscus sabdariffa 200 mg, D-mannose 1000 mg, and Lactobacillus plantarum Lp-115 (1 billion colony forming units) daily for 15 days each month for 6 months (101734); the other study used a specific product (Monurelle Plus, Zambon Italia) containing Hibiscus sabdariffa 100 mg, xyloglucan 100 mg, gelatin 50 mg, and propolis 100 mg twice daily for 14 days (101735). Also, a small observational study in patients with an uncomplicated UTI has found that taking two tablets of a specific combination product (Acidif plus) containing Hibiscus sabdariffa extract 100 mg, boswellia gummy dry extract 100 mg, and L-methionine 400 mg daily for 7 days is associated with reduced UTI symptoms and reduced bacteriuria when compared with taking an unreported dose of fosfomycin for two days (103783). However, due to the poor quality of these studies, the magnitude of benefit is unclear. Also, it is unknown whether these effects are due to Hibiscus sabdariffa, other ingredients, or the combination.
• Wound healing. Although there has been interest in using topical Hibiscus sabdariffa for wound healing, there is insufficient reliable information about the clinical effects of Hibiscus sabdariffa for this purpose.

  More evidence is needed to rate Hibiscus sabdariffa for these uses.

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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 used orally in amounts commonly found in foods. Hibiscus sabdariffa has Generally Recognized As Safe (GRAS) status for use in foods in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Hibiscus sabdariffa tea has been safely consumed in amounts of up to 720 mL daily for up to 6 weeks (16894,93805,93814). Hibiscus sabdariffa extracts, including a specific Hibiscus sabdariffa leaf extract (Green Chem), have also been safely used in doses of up to 1000 mg daily for up to 90 days (17415,54989,93805,93809,105307).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. Hibiscus sabdariffa calyx powder has been used with apparent safety at a dose of 2 grams three times daily for 4 weeks by adolescents aged 12-18 years (93816).

PREGNANCY: POSSIBLY UNSAFE
when used orally. Hibiscus sabdariffa is thought to be a menstrual stimulant, and might have abortifacient effects (19).

LACTATION: POSSIBLY UNSAFE
when used orally in large amounts. Animal research found that administering large doses of Hibiscus sabdariffa during lactation decreases food and water intake during pregnancy and delays puberty in offspring (93810); however, this has not been assessed in humans.

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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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ACETAMINOPHEN (Tylenol, others) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking Hibiscus sabdariffa with acetaminophen might decrease the clinical effects of acetaminophen.  Details There is some evidence that consuming a Hibiscus sabdariffa beverage (Zobo drink) before taking acetaminophen can decrease the elimination half-life of acetaminophen. Hibiscus sabdariffa does not seem to decrease maximum concentration or area under the curve of acetaminophen (12184). The clinical significance of this is unknown.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking Hibiscus sabdariffa with antidiabetes drugs might increase the risk of hypoglycemia.  Details Most clinical research shows that Hibiscus sabdariffa can reduce blood glucose levels (54999,105304,105305).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking Hibiscus sabdariffa with antihypertensive drugs might increase the risk of hypotension.  Details Most clinical evidence suggests that taking Hibiscus sabdariffa reduces systolic and diastolic blood pressure (16894,54985,54995,105304). In animal research, Hibiscus sabdariffa increased the hypotensive effects of single doses of losartan and amlodipine (102459,107901).

CHLOROQUINE (Aralen) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Taking Hibiscus sabdariffa tea along with chloroquine seems to reduce levels of chloroquine.  Details When taken together, Hibiscus sabdariffa tea significantly reduces the bioavailability of chloroquine (55004). This may reduce its clinical effects. People taking chloroquine for the treatment or prevention of malaria should avoid Hibiscus sabdariffa tea.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Hibiscus sabdariffa extract might reduce the metabolism of CYP1A2 substrates.  Details In vitro research shows that Hibiscus sabdariffa calyx extract inhibits CYP1A2 (93811). This interaction has not been reported in humans.

CYTOCHROME P450 2A6 (CYP2A6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Hibiscus sabdariffa extract might reduce the metabolism of CYP2A6 substrates.  Details In vitro research shows that Hibiscus sabdariffa calyx extract inhibits CYP2A6 (93811). This interaction has not been reported in humans.

CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Hibiscus sabdariffa extract might reduce the metabolism of CYP2B6 substrates.  Details In vitro research shows that Hibiscus sabdariffa calyx extract inhibits CYP2B6 (93811). This interaction has not been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Hibiscus sabdariffa extract might reduce the metabolism of CYP2C19 substrates.  Details In vitro research shows that Hibiscus sabdariffa calyx extract inhibits CYP2C19 (93811). This interaction has not been reported in humans.

CYTOCHROME P450 2C8 (CYP2C8) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Hibiscus sabdariffa might reduce the metabolism of CYP2C8 substrates.  Details In vitro research shows that Hibiscus sabdariffa calyx extract inhibits CYP2C8 (93811). This interaction has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Hibiscus sabdariffa extract might reduce the metabolism of CYP2C9 substrates.  Details In vitro research shows that Hibiscus sabdariffa calyx extract inhibits CYP2C9 (93811). This interaction has not been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Hibiscus sabdariffa extract might reduce the metabolism of CYP2D6 substrates.  Details In vitro research shows that Hibiscus sabdariffa calyx extract inhibits CYP2D6 (93811). This interaction has not been reported in humans.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Hibiscus sabdariffa extract might reduce the metabolism of CYP2E1 substrates.  Details In vitro research shows that Hibiscus sabdariffa calyx extract inhibits CYP2E1 (93811). This interaction has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Hibiscus sabdariffa extract might reduce the metabolism of CYP3A4 substrates.  Details In vitro research shows that Hibiscus sabdariffa calyx extract inhibits CYP3A4 (93811). This interaction has not been reported in humans.

DICLOFENAC (Voltaren, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking Hibiscus sabdariffa with diclofenac may increase the levels and adverse effects of diclofenac.  Details Pharmacokinetic research in humans shows that drinking a beverage made with Hibiscus sabdariffa flowers reduces the excretion of diclofenac by approximately 38% when compared with water. The clinical significance of this is unknown (101726).

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Hibiscus sabdariffa might increase the levels and clinical effects of losartan.  Details Animal research in rats with laboratory-induced hypertension shows that providing Hibiscus sabdariffa for 14-17 days prior to a single administration with losartan modestly increases losartan concentrations and increases hypotensive effects when compared with a single administration of losartan alone (102459). It is not clear if Hibiscus sabdariffa alters the concentration or effects of losartan when taken continuously. Additionally, this interaction has not been shown in humans.

SIMVASTATIN (Zocor) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Taking Hibiscus sabdariffa with simvastatin might reduce the levels and clinical effects of simvastatin.  Details A pharmacokinetic study in humans shows that taking a beverage prepared with dried Hibiscus sabdariffa flower 300 grams concurrently with a single dose of simvastatin 40 mg increases the clearance of simvastatin by about 45% and reduces peak levels of simvastatin by 18% (96270).

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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, Hibiscus sabdariffa is generally well tolerated.

Gastrointestinal ...Orally, taking a specific Hibiscus sabdariffa leaf extract (Green Chem) 1 gram daily has been associated with reports of transient gastrointestinal symptoms such as abdominal distention, flatulence, and epigastric pain in one clinical trial. However, the overall rate of these adverse effects was similar to placebo (17415). Taking Hibiscus sabdariffa calyx extract 6 grams daily has been associated with single cases of nausea in one clinical trial (55000). Taking Hibiscus sabdariffa calyx powder 6 grams daily has been associated with reports of mild and transient constipation in one clinical trial (93816). Taking 0.5-1 liters of tea daily, made by steeping 10-15 grams of dried Hibiscus sabdariffa calyces, has been associated with one report of stomach pain in one clinical trial (101733).

Genitourinary ...Orally, taking Hibiscus sabdariffa calyx extract 6 grams daily has been associated with one report of dysuria in one clinical trial (55000).

Neurologic/CNS ...Orally, taking Hibiscus sabdariffa calyx extract 3 grams daily has been associated with one report of tremor and headache in one clinical trial (55000).

Ocular/Otic ...Orally, taking Hibiscus sabdariffa calyx extract 3 grams daily has been associated with one report of tinnitus in one clinical trial (55000).

Pulmonary/Respiratory ...Taking 0. 5-1 liters of tea daily, made by steeping 10, 15, or 20 grams of dried Hibiscus sabdariffa calyces, has been associated with two reports of dyspnea in one clinical trial. A clear association with Hibiscus sabdariffa could not be made (101733).

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