Lecithine Et Carthame (Lecithin and Safflower Seed) by Vitaminol Inc.

POSSIBLY EFFECTIVE

• Hypercholesterolemia. Several small studies suggest that oral safflower oil, as a substitute for coconut oil, butter, or other animal fats in the diet, may reduce total and low-density lipoprotein (LDL) cholesterol levels in patients with or without hypercholesterolemia. Details: Three small clinical studies in patients with or without hypercholesterolemia show that substituting coconut oil, butter, or other animal fats in the diet with safflower oil (36% of total daily calories) for 4-6 weeks can lower levels of total and LDL cholesterol, but has no beneficial effects on high-density lipoprotein (HDL) cholesterol or triglycerides (25391,25393,72310).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Coronary heart disease (CHD). Safflower oil, which is high in oleic acid, may be beneficial for reducing the risk of CHD when used to replace other dietary oils. Details: Some safflower oil products contain high quantities of oleic acid. In 2018, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that consuming 1.5 tablespoons daily of oils containing at least 70% oleic acid may reduce the risk of CHD. In order to obtain any benefit, this oil must be used to replace fats and oils higher in saturated fat. However, the FDA has determined that this statement is based on supporting, rather than conclusive, evidence (98563).
• Cystic fibrosis. It is unclear if oral safflower oil is beneficial in children with cystic fibrosis. Details: A very small clinical study in children with cystic fibrosis shows that taking safflower oil 1 gram/kg daily for one year does not affect sweat chloride concentrations or disease severity when compared with age-matched controls (72281).
• Diabetes. Small clinical studies of oral safflower oil for improving glycemic control in patients with diabetes have yielded mixed results. Details: One very small clinical trial in patients with type 2 diabetes shows that taking safflower oil 10 grams daily for 3 weeks increases fasting blood glucose by 11% when compared to baseline. Insulin levels, insulin sensitivity, and lipid levels were not affected (13146). However, another small clinical study in obese, postmenopausal patients with type 2 diabetes shows that taking safflower oil 2 grams four times daily for 16 weeks decreases HbA1c by 0.64% and increases high-density lipoprotein (HDL) cholesterol by about 5 mg/dL when compared with conjugated linoleic acid (CLA) 2 grams four times daily. Insulin sensitivity and fasting blood glucose levels do not appear to be affected (94039). These differing outcomes may be due to the small study sizes and varied patient populations.
• Diabetic nephropathy. Small clinical studies suggest that intravenous safflower yellow, a component of safflower flower, might improve symptoms and markers of diabetic nephropathy. Details: A meta-analysis of 14 small and low-quality clinical studies in adults with diabetic nephropathy shows that intravenous administration of safflower yellow as an adjunct to conventional treatment reduces urinary albumin excretion rate, fasting blood glucose, serum creatinine, and blood urea nitrogen when compared with conventional treatment alone. Overall, patients receiving safflower yellow were more likely to experience a clinical improvement in symptoms when compared with conventional treatment alone (102381).
• Familial hypercholesterolemia. Small clinical studies suggest that substituting safflower oil in place of butter in the diet may modestly reduce cholesterol levels in patients with familial hypercholesterolemia. Details: Two very small clinical studies in patients with familial hypercholesterolemia show that substituting safflower oil in place of butter in the diet (contributing 36% of daily calories) for 3 weeks decreases total and low-density lipoprotein (LDL) cholesterol levels when compared with butter (72246,72267).
• Hepatitis C. Oral safflower oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, open-label clinical study in patients with chronic hepatitis C shows that taking a specific combination product containing safflower, pumpkin seeds, plantain seeds, and Japanese honeysuckle (EH0202) 1 gram daily for 3 months modestly reduces general discomfort, abdominal bloating, nausea, and vomiting when compared to baseline. However, hepatitis C RNA and hepatitis C virus antibody levels are not affected (72238).
• Hypertension. It is unclear if oral safflower oil is beneficial for reducing blood pressure; the available research is conflicting. Details: A very small clinical study in patients with hypertension shows that taking safflower oil 10 mL twice daily for 6-8 weeks reduces diastolic blood pressure when compared with placebo (72304). However, another small clinical study in patients with mild hypertension shows that taking safflower oil 30 mL daily for 6 weeks does not affect blood pressure when compared to baseline (72268).
• Low birth weight. It is unclear if oral safflower oil is beneficial in infants with low birth weight. Details: A small clinical study in low birth weight infants shows that fortifying formula or breast milk with a specific safflower oil product (Safola, Marico Industries Ltd.) does not improve weight gain or skin thickness when compared with coconut oil or unfortified formula or breast milk (72229).
• Metabolic syndrome. It is unclear if oral safflower oil is beneficial in patients with metabolic syndrome. Details: A small clinical study in patients with metabolic syndrome shows that taking safflower oil 2 grams four times daily for 12 weeks reduces waist circumference by 3.4 cm, systolic blood pressure by 7 mmHg, diastolic blood pressure by 3 mmHg, and fasting blood glucose by 8 mg/dL when compared with placebo. However, body weight, body mass index (BMI), and lipid levels were not affected (108889).
• Obesity. Although there has been interest in using oral safflower oil for obesity, there is insufficient reliable information about the clinical effects of safflower oil for this purpose.
• Myocardial infarction. Intravenous safflower yellow, a component of safflower flower, might improve outcomes when used as an adjunct to conventional therapy for the treatment of acute coronary syndrome (ACS). Details: A meta-analysis of 16 small, low-quality clinical trials in patients with ACS, including myocardial infarction and unstable angina, shows that intravenous administration of safflower yellow 20-40 mL daily for 10-15 days as an adjunct to conventional therapy improves clinical outcomes, electrocardiogram measures, and left ventricular ejection fraction when compared with placebo (108891).
• Phrynoderma. It is unclear if oral safflower oil is beneficial in patients with phrynoderma. Details: A small clinical study in patients with phrynoderma shows that taking 30 mL of safflower oil containing vitamin E 116 mg and linoleic acid 68% daily for more than 8 weeks can partially improve skin dryness and roughness when compared to baseline (72269). The validity of these findings is limited by the lack of a comparator group.
• Scarring. Topical safflower oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with non-hypertrophic scars and striae shows that applying an oil containing safflower oil 55.9%, olive oil 42%, grapefruit oil 2%, and tocopherol 0.1% (Kneipp Bio Skin Oil, Kneipp GmbH) to the scars and striae twice daily for 8 weeks improves scores on the Patient Scar Assessment Scale (PSAS) by 20%, compared to a 6% improvement in untreated areas (95938).
• Stroke. Small clinical studies suggest that intravenous safflower yellow, a constituent of safflower flower, as an adjunct to conventional treatments, may improve neurological outcomes post-stroke. Details: A meta-analysis of seven small, low-quality clinical studies in Chinese patients with acute ischemic stroke shows that intravenous administration of safflower yellow 100-150 mg as an adjunct to conventional treatments, starting within 72 hours of stroke onset and continuing once daily for 14 days thereafter, increases the odds of neurological improvement by about 3-fold when compared with conventional treatments alone (94038).
• Unstable angina. Intravenous safflower yellow, a component of safflower flower, might improve outcomes when used as an adjunct to conventional therapy for the treatment of unstable angina. Details: A meta-analysis of seven low-quality clinical studies in Chinese patients with unstable angina shows that intravenous safflower yellow 50-150 mg daily for 14-15 days in addition to conventional treatment modestly improves electrocardiogram (ECG) measures and symptoms of angina when compared with conventional treatment alone (94041). Another meta-analysis of 16 small, low-quality clinical trials in patients with acute coronary syndrome (ACS), including unstable angina and myocardial infarction, shows that intravenous administration of safflower yellow 20-40 mL daily for 10-15 days as an adjunct to conventional therapy improves clinical outcomes, ECG measures, and left ventricular ejection fraction when compared with placebo (108891). More evidence is needed to rate safflower for these uses.

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POSSIBLY EFFECTIVE

• Breast cancer. High dietary intake of soy might be beneficial for the prevention of breast cancer and breast cancer recurrence in some patients. However, soy supplements do not seem to be beneficial. Details: For prevention, most population research has found that higher dietary intake of soy is associated with up to a 26% reduced odds of developing breast cancer when compared with a lower intake (7335,7336,11038,11807,75377,75587,90955,108251). One meta-analysis of population research found that patients who consumed more than 15 mg soy isoflavones daily made up about 25% of all cases of breast cancer, compared with 75% of cases in the group of patients consuming less than 15 mg daily (108251). The effects appear to vary depending on the ethnicity of the patient. Population research has consistently found that a high-soy diet in Asian and Asian-American females is associated with a significantly reduced risk of breast cancer (7335,7336,11038,11807,75377,75587,90955). However, the amount of soy consumed in a Western diet, even among those who consume the highest amounts of soy, was not found to have a preventative effect (11391,17109,90955,90967). The reason for the disparate findings are unknown but may be related to genetic differences or differences in quantification of soy intake (7663,94153). Also, the prophylactic benefit seems to apply regardless of whether high amounts of soy are consumed during adolescence or later in life (7335,7336,9674). Limited population research has also found that consuming a diet high in soy is associated with up to a 25% reduced risk of breast cancer recurrence; however, it is unclear whether there is an association with reduced mortality in breast cancer patients (90956,90969,94154). The effect appears to be greater for certain subgroups of breast cancer patients. Increased dietary soy intake is associated with a 28% to 36% risk reduction in patients with estrogen receptor (ER)-negative tumors, a 30% risk reduction in patients with ER-positive/progesterone receptor (PR)-positive tumors, and a 25% to 36% risk reduction in postmenopausal patients (90956). Some small clinical studies have also evaluated the use of soy isoflavone extract . One small clinical study in patients with breast cancer shows that taking a soy isoflavone extract 200 mg daily for 2 weeks prior to surgery does not seem to affect cancer cell growth when compared with a historical control (11042). Another small clinical study in patients at high risk for breast cancer or with a history of breast cancer shows that taking a soy tablet containing 50 mg soy isoflavones (Novasoy, Archer Daniels Midland Co.) daily for 12 months does not alter mammographic or breast tissue density when compared with placebo (95999).
• Chronic kidney disease (CKD). Oral soy protein seems to improve some measures of disease severity in patients with CKD. Details: Clinical research shows that consuming soy protein seems to reduce proteinuria in people with kidney disease (2286,2287,2288,75249,75634). Also, a meta-analysis of clinical research in patients with CKD who are not on dialysis shows that soy protein intake reduces serum levels of creatinine by 0.07 mg/dL, phosphorus by 2.5 mg/dL, and triglyceride by 18 mg/dL when compared with placebo or control (90989).
• Diabetes. Diets high in soy seem to reduce the risk of type 2 diabetes. Also, oral soy protein, but not soy isoflavones, seems to modestly improve glycemic indices. It is unclear if soy is beneficial for lowering blood lipid levels or reducing cardiovascular (CVD) mortality risk in adults with type 2 diabetes. Details: A meta-analysis of observational studies has found that higher dietary intake of tofu, soy protein, or soy isoflavones is associated with an 8% to 16% lower risk of developing diabetes when compared with a lower dietary intake (105608). In menopausal patients without diabetes, a meta-analysis of clinical research shows that intake of soy isoflavones 40-161 mg daily seems to improve glycemic indices when compared with control (96423). Some research shows that soy can modestly improve glycemic indices in patients with diabetes. A meta-analysis of small low-quality clinical studies in patients with diabetes or metabolic syndrome shows that taking various formulations of soy protein modestly reduces fasting plasma glucose and insulin levels, as well as insulin resistance, when compared with control (96001). An older meta-analysis assessing both healthy patients and patients with diabetes shows that a whole soy diet reduces fasting blood glucose by about 4 mg/dL when compared with control (75493). Small clinical studies also suggest that an extract of the fermented soybean product, Touchi, acts as an alpha-glucosidase inhibitor. It seems to modestly lower blood glucose, glycated hemoglobin (HbA1c), and triglycerides in patients with type 2 diabetes (11762,75205). However, some conflicting evidence exists. A meta-analysis of small, low-quality clinical studies in patients with type 2 diabetes shows that taking soy isoflavones does not improve glycemic indices when compared with control (105610). Also, another meta-analysis of clinical research in patients with type 2 diabetes shows that taking soy protein and/or soy isoflavones for 6-12 weeks does not improve glycemic indices when compared with either soy protein without isoflavones, other protein, or placebo (105610). Reasons for these conflicting results are unclear but may relate to differences in baseline blood glucose levels, the formulation of soy, or the duration of treatment. Some research shows that soy may modestly improve the lipid profile in patients with diabetes. A meta-analysis of clinical research in patients with diabetes shows that taking soy protein and/or soy isoflavones for 6-12 weeks modestly reduces levels of total and low-density lipoprotein (LDL) cholesterol, but not high-density lipoprotein (HDL) cholesterol or triglycerides, when compared with control (105610). Consuming soy foods might reduce the risk of mortality related to CVD in patients with diabetes. Population research suggests that consuming soy foods at least four days each week is associated with a 23% reduced risk of CVD mortality when compared with never consuming soy foods. Consuming soy foods less than four times weekly is not associated with CVD mortality risk (108242). Soy is also of interest in the prevention or treatment of gestational diabetes. Population research has found that consumption of less than 40 grams of soy daily in the second trimester is associated with a 2.1-fold increased risk of gestational diabetes when compared with daily soy intake of 40 grams or more (108241). Also, a small clinical trial in patients with gestational diabetes shows that consuming a diet containing about 0.3 grams/kg soy protein for 6 weeks, beginning at 24-28 weeks' gestation, reduces blood glucose levels, insulin resistance, and triglyceride levels when compared with consuming a non-soy control diet (95993).
• Diarrhea. Oral soy fiber seems to reduce acute diarrhea in infants, although it may not be beneficial in adults. Details: Giving soy fiber-supplemented formula orally, either alone or in combination with oral rehydration solution, seems to reduce the duration of acute diarrhea in infants when compared with cow's milk formula or oral rehydration solution alone (2291,2292,75474,75517,75523,75531,75572). However, in some studies, a reduction in the duration of acute diarrhea was not observed when compared with cow's milk formula (75522,75542). In adult patients receiving nutrition via intubation, preliminary clinical research suggests that treatment with soy-polysaccharide fiber does not improve the incidence of diarrhea when compared to control (75508).
• Galactosemia. Oral soy protein can be used in infant formula to prevent symptoms of galactosemia. Details: Soy does not contain the sugar galactose. Some research suggests that giving oral isolated soy protein-based formula in place of milk-based formula to infants seems to be helpful for preventing symptoms of galactosemia (3400).
• Hyperlipidemia. Oral soy protein seems to modestly reduce lipid levels. However, purified soy isoflavone may not have the same benefit. Details: Consuming soy protein orally, in place of other dietary protein, seems to modestly reduce total cholesterol and low-density lipoprotein (LDL) cholesterol by about 3% to 4% when compared with control (842,2293,2294,2296,2585,3402,4755,6412,7346,7803)(8530,10459,42059,75356,105598,105604). Additionally, some research shows that soy protein might be more effective in patients with more severe hyperlipidemia (75497). The FDA has approved labeling for specific soy products that states that they may be used for cholesterol reduction in combination with a diet low in saturated fat and cholesterol. To be eligible for this labeling, soy products must provide at least 6.25 grams of soy protein per serving, which is 25% of the effective daily intake (3977). However, not all evidence is positive. Some studies have shown no benefit of soy protein or isoflavones on LDL cholesterol levels when compared to control (8521,9679,12034,17105,53771,75236)(75242,75274,75276). Furthermore, although a few clinical trials have shown significant decreases in triglycerides following supplementation with soy or soy protein isolate (75258,75365), most studies suggest that soy protein does not decrease triglycerides when compared to control (2293,6412,8530,12034,17105). The effect of soy protein on high-density lipoprotein (HDL) cholesterol is inconsistent. Most studies suggest that it does not increase HDL levels (2293,6412,8530,12034,75286)(75524), although some analyses of clinical research suggest that soy might increase HDL cholesterol levels by up to 4% when compared to control (75480,75497). Doses of soy protein have ranged from 25-135 grams daily, providing 40-318 mg daily of isoflavones; however, higher doses do not seem to be more effective (17106,105598). Some evidence suggests that soy protein providing more isoflavones, or supplemented with isoflavones, might be more effective (3402,6413,10459), but this has not been consistently found in studies (3402). Most studies evaluating soy protein products containing little to no isoflavones suggest that these products are not effective (3402,7346,9679); however, purified soy isoflavone supplements alone do not seem to decrease LDL cholesterol (851,4738,7345,8502,10459,14066). In addition to soy protein, limited evidence suggests that soy fiber alone might reduce total cholesterol, LDL cholesterol, and triglyceride levels when compared with placebo (75686,75689). There is also some evidence that ultra-high temperature (UHT) treatment of soy milk destroys any cholesterol-lowering activity (17106).
• Hypertension. Oral soy seems to modestly reduce blood pressure in some patients. Details: A meta-analysis of the available clinical research shows that consuming soy products modestly lowers systolic and diastolic blood pressure by an average of 1.6 mmHg and 1.2 mmHg, respectively, when compared with control (105605). This analysis is limited by high risk of bias and the lack of a dose-response relationship. An older meta-analysis, as well as individual clinical studies, in patients with prehypertension or mild hypertension show that consuming soy protein 18-40 grams, providing 118-143 mg of isoflavones, daily or black soy peptide 4.5 grams daily for 8 weeks reduces systolic blood pressure by about 4-8 mmHg and diastolic blood pressure by about 3-5 mmHg when compared with control (1313990962,90965). In normotensive patients, soy protein does not seem to reduce systolic or diastolic blood pressure (90965).
• Lactose intolerance. Oral soy protein can be used in infant formula to prevent symptoms of lactose intolerance. Details: Providing isolated soy protein-based formula orally to infants is an acceptable alternative to milk-based formulas, especially for infants with symptoms of lactose intolerance (3400).
• Menopausal symptoms. Oral soy seems to reduce hot flashes in patients with menopausal symptoms. Details: Consuming soy protein 15-60 grams, providing 34-100 mg of isoflavones, daily seems to modestly decrease the frequency and severity of hot flashes in some menopausal adults. Improvement seems to be greater in those with a higher frequency of hot flashes at baseline (2296,2297,3978,3986,3987,7653,9917,11805,15220,17110,75478)(75486,75649,92661,95997). Taking concentrated soy isoflavone extracts, providing 35-200 mg of isoflavones, daily seems to have similar effects (4751,6455,7802,9916,10460,11805,11993,11994,13209,15220)(15850,75478,90950,90979,92661). Higher doses of 100-200 mg of isoflavones daily and higher frequency of dosing intervals seem to have greater benefit (90950). Furthermore, the amount of the specific isoflavone genistein contained in a soy product may influence outcomes. According to one analysis, studies using products that provide at least 15 mg of genistein daily consistently show positive outcomes. Studies using products containing a lower concentration of genistein have produced inconsistent findings (15133). Not all research has found that soy extracts reduce hot flashes (7801,11806,14062,15038,15851,16762); some experts speculate that this is due to a high placebo response (9916). Some clinical research has compared soy isoflavone extracts to conventional estrogen replacement. In one study, a concentrated soy isoflavone extract of genistein 54 mg daily reduced hot flashes by 22% to 29%, compared to 54% in those taking 17beta-estradiol as 1 mg daily plus norethisterone acetate 0.5 mg daily (11994). Additional preliminary research suggests that taking a soy isoflavone extract providing 60 mg isoflavones twice daily is comparable in efficacy to conjugated estrogens 0.625 daily for reducing menopausal symptoms. Conjugated estrogens seem to work more quickly; it seems to take up to 2 months to achieve the full effect of soy isoflavones (13209). One clinical trial compared soy isoflavones 10-40 mg daily to S-equol, a soy isoflavone metabolite. Soy isoflavones were less effective for reducing hot flash frequency when compared with S-equol (90960). This has led to some speculation that the effectiveness of soy in relieving hot flashes is influenced by a patient's ability to convert daidzen, a soy isoflavone, to S-equol (90950). It is theorized that patients who are S-equol producers are more likely to achieve symptom relief from soy. However, observational and clinical research does not support this theory (90990,94162). Soy has also been evaluated for the management of other symptoms of menopause. Some clinical research in menopausal patients with depression suggests that taking soy 100 mg, providing 50 mg of soy isoflavones, in combination with sertraline 50 mg daily for three months improves depression severity when compared with sertraline or soy alone (90958). An analysis of two small clinical trials shows that supplemental soy providing 50-118 mg of isoflavones can reduce vaginal dryness scores by 0.26 when compared with control (92661). Also, an open-label study suggests that drinking a specific beverage (ViveSoy) containing soy protein 15 grams and soy isoflavones 50 mg orally daily for 12 weeks reduces overall urogenital symptoms when compared with a control group (95997). However, one small clinical study in perimenopausal patients shows that a soy-rich diet does not relieve urogenital symptoms, including vaginal dryness, itching, and urinary incontinence, when compared with a soy-free diet (75285).
• Metabolic syndrome. Oral soy protein seems to improve glycemic control and other markers of metabolic syndrome. Details: A meta-analysis of clinical research in patients with diabetes or metabolic syndrome shows that following a diet high in soy protein can decrease fasting plasma glucose and insulin levels, as well as insulin resistance, when compared with a control diet. Furthermore, dietary intake of soy protein modestly decreases diastolic blood pressure and low-density lipoprotein (LDL) cholesterol by a small amount in this population, although there is no effect on systolic blood pressure, high-density lipoprotein (HDL) cholesterol, or triglycerides (96001). Other clinical research shows that consuming a soy nut diet or a soy protein diet reduces fasting plasma glucose and LDL cholesterol levels when compared to baseline in postmenopausal adults with metabolic syndrome; however, the soy nut diet seems to more beneficial than either the soy protein diet or a Dietary Approaches to Stop Hypertension (DASH) diet (75378).
• Muscle strength. Oral soy protein seems to increase muscle strength. Details: Overall, soy protein combined with resistance training seems to increase muscle strength when compared with placebo (16748,75246,96942,98871). A meta-analysis of three clinical studies shows that consuming soy protein in addition to resistance training improves strength and lean body mass in untrained athletes (98871). Other clinical research shows that soy also improves muscle strength in trained athletes and postmenopausal adults (75246,96942). One study in Olympic endurance athletes shows that consuming isolated soy protein (Supro) 1.5 grams/kg daily for 8 weeks increases body mass and strength indices and reduces fatigue when compared with no protein supplementation (75246). Clinical research in postmenopausal adults undergoing resistance training 3 days weekly shows that taking soy protein 25 grams daily in skim milk for 16 weeks increases the maximum amount of weight lifted in one repetition by over 80% for both bench press and knee extension when compared to a maltodextrin placebo (96942). Soy protein has also been compared with other protein supplements. A meta-analysis of preliminary clinical studies and other clinical research show that soy protein seems to work as well as whey, beef, and dairy (casein and whey) protein for improving muscle strength (75404,85941,98871,105591). However, the validity of these findings is limited by the small size and high heterogeneity of the studies.
• Osteoporosis. Oral soy isoflavones seem to improve bone density and reduce the risk of osteoporosis in post-menopausal adults. Details: Most clinical research suggests that soy protein or soy extract containing 75-90 mg of isoflavones can increase bone mineral density (BMD), or slow BMD loss, and improve biochemical markers of bone turnover in peri- and postmenopausal adults when compared with control (842,4951,6449,9775,11082,90972,90980). Lower doses of isoflavones do not seem to be as beneficial. However, some observational research in postmenopausal Japanese adults and Chinese females aged 30-40 years has found that consuming about 50 mg dietary soy isoflavones daily is associated with a higher BMD when compared with lower soy isoflavone intake (7342,11081). An observational study in postmenopausal Asian patients has found that consuming higher dietary soy protein is associated with a lower risk of developing fractures when compared with lower amounts (13181). However, not all research has been positive. Some conflicting evidence suggests that soy protein does not improve BMD in some postmenopausal adults. The discrepancy in findings may be due to differences in soy formulations, concomitant treatments, or variable patient populations (4952,12034,14064,90978). For example, most evidence shows that soy does not affect BMD in premenopausal patients or bone turnover in adolescents (7660,8532,9684,11086). It is theorized that only people who can convert daidzein, a soy isoflavone, to S-equol might obtain benefits from soy (4952). However, clinical research suggests that there is no difference in bone calcium retention between equol producers and nonproducers (95995).

POSSIBLY INEFFECTIVE

• Benign prostatic hyperplasia (BPH). Oral soy does not seem to reduce BPH symptoms. Details: Clinical research in patients with BPH shows that taking soy isoflavones 40 mg (Soylife 40, Acatris) daily for 12 months does not improve peak urine flow rate, residual urine volume, symptoms of BPH, or general quality of life when compared with placebo (90983).
• Breast cancer-related hot flashes. Oral soy does not seem to reduce the risk for breast cancer-related hot flashes. Details: Clinical research shows that consuming a soy beverage providing soy isoflavones 90 mg daily or taking a soy extract providing soy isoflavones 50 mg three times daily does not reduce hot flashes in breast cancer survivors (3991,7658,8499). Observational research in breast cancer survivors has also found no association between hot flash incidence and soy isoflavone consumption (105602).
• Colorectal cancer. Oral soy does not seem to reduce the risk for colorectal cancer. Details: Some observational research from China and Japan has found that intake of soy protein or soy isoflavone is not associated with the risk of developing colorectal cancer (105601). Furthermore, some clinical research shows that soy protein powder 58 grams containing isoflavones 83 mg, taken daily for 12 months, does not reduce the proliferation of colorectal epithelial cells in patients with adenomatous polyps when compared to control (75282).
• Exercise-induced muscle soreness. Oral soy does not seem to reduce muscle soreness after exercise. Details: Some clinical research shows that taking soy isoflavone extract 120 mg orally for 30 days prior to exercise doesn't ameliorate muscle soreness caused by exercise when compared with placebo (8524).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. It is unclear if oral soy improves cognition in patients with Alzheimer disease. Details: Preliminary clinical research in patients with Alzheimer disease shows that taking soy isoflavones (Novasoy, Archer Daniels Midland Co.) 100 mg daily for 6 months does not improve cognition when compared with placebo (96424).
• Androgen deprivation therapy (ADT)-associated hot flashes. One small clinical study in patients with prostate cancer receiving ADT shows that taking soy protein powder 20 grams, providing 160 mg of isoflavones, alone or along with venlafaxine 75 mg, once daily for 12 weeks does not improve the severity of hot flash symptoms when compared with milk protein, with or without venlafaxine (90981).
• Asthma. It is unclear if oral soy reduces asthma symptoms. Details: One population study has found that people with asthma who consume soy foods providing more than 250 mcg of genistein for every 1000 kcal consumed (e.g., 500 mcg/day for 2000 kcal diet) daily have increased lung function, as measured by FEV1 scores, when compared to those who consume less (11084). However, clinical research in adult and pediatric patients with poorly controlled asthma shows that taking soy isoflavones 50 mg twice daily for 24 weeks does not improve FEV1 scores, reduce the number of asthma episodes, or improve asthma symptoms when compared with placebo (90977).
• Cardiovascular disease (CVD). It is unclear if soy consumption reduces the risk for CVD or CVD-related mortality. More research is needed to determine whether certain populations may benefit from increased soy intake. Details: Due to mixed findings, it is unclear if consuming soy is associated with a reduced risk of CVD events. One population study has found that consuming at least 60 grams of soy daily over a 12-month period is associated with a 14% reduced risk of having a CVD event over the next 5 years, as well as a reduced risk of stroke, when compared with consuming less than 15 grams daily (108253). A study in Japan has found that consuming soy five or more times per week over a 10-year period is associated with fewer adverse cardiovascular outcomes in only a certain subset of patients when compared with consuming soy twice a week or less. Postmenopausal adults with the highest consumption had a 36% lower risk of stroke, a 45% lower risk of myocardial infarction, and a 65% lower risk of CVD mortality. However, risk was not significantly reduced in males or premenopausal adults (17108). In contrast, a study in Korea has found that consuming a median of 16.5 servings of soy per week is associated with a 64% reduced risk of CVD incidence in premenopausal, but not postmenopausal, adults when compared with a median of 4.7 servings per week. A subgroup analysis has found that the highest intake of tofu, but not soybeans, fermented soy paste, or soy milk, is associated with a reduced incidence of CVD (108243). Additionally, higher dietary intake of soy does not seem to be associated with a reduced risk of cardiovascular events in Western females (13040). The amount of phytoestrogens typically consumed in Western diets is significantly lower than the amount typically consumed in Asian diets. The form of soy food and isoflavone content might play a role in these discrepancies. Any association between consumption of soy-containing foods and CVD mortality is also unclear. A meta-analysis of observational studies conducted in China or Japan has found that the highest intake of soy-containing foods is not associated with a lower risk of CVD-related mortality when compared with the lowest intake (96941). A population study in patients with or without a prior history of CVD has also found that soy-containing food consumption is not associated with a lower risk of CVD-related mortality when compared with the lowest intake (108244). However, some research has found a positive effect of soy consumption on CVD mortality risk. A subgroup analysis of a meta-analysis has found that the highest intake of fermented soy products is associated with a 16% reduced risk of CVD mortality; higher intake of non-fermented soy is not associated with CVD mortality (96941). Population research in patients without a prior history of CVD has found that soy-containing food consumption is associated with a lower risk of myocardial infarction-related mortality when compared with the lowest intake (108244). Also, one population study in adults with type 2 diabetes has found that consuming soy-containing foods at least four days each week is associated with a 23% reduced risk of CVD mortality when compared with never consuming soy foods. Consuming soy foods less than four times weekly is not associated with CVD-related mortality (108242).
• Cervical cancer. It is unclear if oral soy reduces the risk for cervical cancer. Details: Population research has found that the highest dietary intake of soy over approximately 17 years is associated with a 57% decreased risk of cervical cancer when compared to the lowest intake of soy in females who also drank green tea. However, neither soy intake nor green tea intake alone was associated with a decreased risk of cervical cancer. Additionally, other population research has not confirmed an association between soy intake and cervical cancer (101800).
• Child growth. It is unclear if oral soy protein enhances child growth. Details: Preliminary clinical research in Colombian children 2-7 years of age shows that consuming a soy protein supplement dissolved in fruit juice on 6 days of every week for 1 year does not improve body mass index, body composition, weight, or height when compared with consuming fruit juice and whole milk. A sub-analysis shows that children consuming the soy protein supplement had an increase in weight-for-age when compared with the control group, indicating that the supplement may be beneficial for ensuring adequate weight and nutritional status during prepubertal growth (100320). However, the children in this study had normal or below average weight-for-age at baseline, limiting the applicability of these findings to other patient populations.
• Cognitive function. It is unclear if oral soy improves cognitive function; research is conflicting. Details: Some research shows that college students who increase consumption of soy foods providing isoflavones 100 mg daily have improved short- and long-term memory (9671). Postmenopausal patients aged 50-65 years who take a soy extract supplement providing isoflavones 60 mg daily also seem to have some improvement in some measures of cognitive function (12048). There is also evidence in postmenopausal patients aged 55-75 years that taking a soy extract supplement providing isoflavones 110 mg daily might improve verbal memory scores (12040). However, another study in this population shows that consuming 25.6 grams daily of soy protein providing 99 mg of isoflavones does not improve cognitive function (12034). Similarly, population research in females aged 42-52 years has found that increasing dietary intake of the isoflavones genistein and daidzein is not associated with improved measures of cognitive function (15042). These differing findings might be explained by variations in study design and soy formulations.
• Cognitive impairment. Oral soy has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults 55 years of age and older with mild cognitive impairment shows that taking a specific combination product (DW2009) containing fermented soybean powder and Lactobacillus plantarum daily for 12 weeks modestly improves composite cognitive function when compared with placebo (100319). It is not clear if this effect is due to soy, lactobacillus, or the combination.
• Colic. It is unclear if oral soy is beneficial in infants with colic. Details: Preliminary clinical research shows that consuming soy-based formula might reduce the duration of colic symptoms in infants with cows' milk intolerance (75509,75543). However, other clinical research shows that consuming soy-based formula does not improve crying in infants with colic when compared with dicyclomine hydrochloride 3 mg/kg daily (75573). Also, a meta-analysis of only high quality clinical research shows that soy milk formula does not improve the persistence of colic or the duration of crying in infants with colic when compared with control (75611).
• Crohn disease. It is unclear if oral soy improves symptoms of Crohn disease. Details: A small observational study in patients with inactive Crohn disease has found that taking oral soy-derived protein in combination with enteral treatment for 4 weeks is associated with increased bowel movements, improved symptoms such as fatigue and mental strain, and increased body weight when compared with standard enteral treatment alone (75175).
• Diabetic nephropathy. It is unclear if oral soy improves kidney function in patients with diabetic nephropathy. Details: A meta-analysis of small clinical trials in patients with diabetic nephropathy shows that consuming soy products, such as soy protein and soy milk, modestly reduces proteinuria and blood urea nitrogen (BUN), as well as levels of total and low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting blood glucose, when compared with animal protein or cow's milk. However, there was no effect on any measures of kidney function (108247). Some individual small clinical trials show that replacing dietary animal protein with soy protein reduces urinary albumin excretion in patients with diabetic nephropathy (7348,12555,12556). However, one small clinical study shows that consuming soy milk 240 mL daily for 4 weeks does not affect urinary creatinine, blood urea nitrogen, proteinuria, or glomerular filtration rate in patients with diabetic nephropathy (90966).
• Dyspepsia. Oral soy protein has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with mild or moderate dyspepsia shows that consuming 1 gram of toasted soy flour fermented with Lactobacillus delbrueckii up to three times daily for 3 weeks does not improve heartburn severity or frequency when compared with placebo (105599).
• Endometrial cancer. It is unclear if oral soy protein reduces the risk for endometrial cancer. Details: Most epidemiological research has found that increased soy intake is associated with a lower risk of endometrial cancer. Endometrial cancer incidence is lower in Japan, China, and other Asian countries where the typical diet is low in calories and high in soy, whole grain foods, vegetables, and fruits (7338,11036,90954). Also, a large meta-analysis of population research has found that the highest total and fermented soy intake is associated with a 17% to 19% reduced risk of developing endometrial cancer when compared to the lowest intakes in postmenopausal adults (96002). However, one clinical study shows that taking soy protein 25 grams daily providing 91 mg of aglycon equivalents of isoflavones and glycosides for three years does not reduce the risk of endometrial hyperplasia or cancer when compared with placebo in postmenopausal adults. However, this study may not have been adequately powered to detect small differences in the low rates of endometrial hyperplasia (90971).
• Fibromyalgia. It is unclear if oral soy reduces fibromyalgia symptoms. Details: Clinical research shows that consuming a shake containing soy protein 20 grams and soy isoflavone 160 mg once daily for 6 weeks does not improve physical functioning or symptoms of depression in patients with fibromyalgia when compared with placebo (75451).
• Gastric cancer. It is unclear if oral soy reduces the risk for gastric cancer. Details: Meta-analyses of population research have found that the highest intake of soy-containing foods and nonfermented soy products is associated with a 21% to 37% decreased risk of gastric cancer when compared with the lowest intake (95998,108246). Intake of at least 100 grams daily of nonfermented soy foods was found to be the most protective (95998). However, a high intake of fermented soy products is associated with an increased risk of gastric cancer, and intake of 1-5 cups daily of the fermented soy product miso soup is associated with an increased risk of gastric cancer in males (95998,108246).
• Hepatitis C. It is unclear if oral soy is beneficial for hepatitis C. Details: Preliminary clinical research in patients with hepatitis C shows that taking soy protein 32 grams daily for 12 weeks reduces the number of cases of steatosis by 47% and reduces alanine aminotransferase (ALT) levels by 13% when compared to baseline. However, it is no different than taking casein protein (90970).
• Irritable bowel syndrome (IBS). A small study suggests that oral soy isoflavones might reduce IBS symptoms. Details: A small clinical study in females with IBS shows that taking soy isoflavones 40 mg daily for 6 weeks improves symptoms of IBS, such as abdominal distention and abdominal pain severity and duration, by approximately 27% when compared with placebo. Quality of life is also improved. Some symptoms are also improved when soy isoflavones are taken in combination with vitamin D; however, the combination of soy isoflavones and vitamin D does not seem to improve symptoms better than soy isoflavones alone (96425).
• Lung cancer. It is unclear if dietary soy reduces the risk for lung cancer. Details: A meta-analysis of epidemiological research has found that although increased soy intake is not associated with a reduced risk of lung cancer overall, it is associated with a slightly reduced risk in nonsmoking adults (90985).
• Mastalgia. It is unclear if oral soy is beneficial for mastalgia. Details: A small clinical study suggests that soy milk providing 34 grams soy protein daily might reduce cyclical breast pain when compared with no intervention (2428).
• Migraine headache. Oral soy has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of soy isoflavones 60 mg, dong quai 100 mg, and black cohosh 50 mg daily for 24 weeks reduces the frequency of menstrual-associated migraine attacks when compared with placebo (35797). It is not clear if this effect is due to soy, the other ingredients, or the combination.
• Neonatal jaundice. It is unclear if oral soy reduces the risk of neonatal jaundice. Details: Clinical research shows that patients with gestational diabetes who consume a diet containing soy protein along with other plant and animal proteins for 6 weeks beginning at 24-28 weeks' gestation have a 73% reduced risk for newborn hyperbilirubinemia when compared with those consuming a control diet containing only non-soy plant and animal proteins (95993).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral soy is beneficial for the treatment or prevention of NAFLD. Details: Observational research in a Chinese population has found that increased frequency of dietary soy consumption is associated with a lower incidence of NAFLD when compared with lower consumption (105612). A meta-analysis of three small clinical trials in patients living in Iran with NAFLD shows that consuming soy milk, soy foods, or a genistein supplement for 8 weeks might reduce some liver transaminase levels when compared with control (105611). Another meta-analysis of small clinical trials in patients with NAFLD shows that consuming soy milk, soy foods, or a genistein supplement for 8 or 24 weeks modestly improves insulin resistance but does not improve body mass index, cholesterol levels, or liver transaminase levels (108239). These analyses are limited by their generally small population size and the heterogeneity of interventions.
• Obesity. It is unclear if consuming oral soy protein as part of a calorie-restricted diet improves weight loss; research is conflicting. Details: Some clinical research shows that consuming soy protein in conjunction with calorie restriction for 2-6 months helps reduce weight in those who are obese and overweight when compared with calorie restriction alone (11085,75397). Other clinical research shows that consuming soy protein for 16 weeks improves weight loss in overweight females when compared with consuming protein from meat (75620). Also, consuming black soy peptide 4.5 grams daily for 12 weeks reduces body weight and body fat mass more than placebo in overweight and obese adults (90961). In addition, some clinical evidence shows that eating biscuits supplemented with soy fiber 100 grams daily for 12 weeks reduces body weight, body mass index (BMI), and low-density lipoprotein (LDL) cholesterol when compared to control in overweight and obese patients (90960). However, contradictory evidence exists. Some clinical research shows that following a calorie-restricted diet and consuming soy-based meal replacements 3-5 times daily for 12-16 weeks, or eating soy protein-rich foods in place of animal protein for 2-12 weeks, does not improve weight loss in overweight or obese individuals when compared to a calorie-restricted diet alone (75277,75372,75376,90968). Also, in overweight and obese females following a free-choice diet, soy protein 56 grams daily for 23 weeks does not appear to improve weight loss when compared to eating an isoenergetic amount of carbohydrates (86077). Finally, a subgroup analysis of six preliminary clinical trials shows that soy products do not improve weight loss in postmenopausal adults (98870). The reason for these disparate findings is unclear but may be due to differences in the soy products used or differences in patient population. For example, a meta-analysis of clinical research shows that phytoestrogen consumption reduces weight in healthy postmenopausal adults but not in those with comorbid conditions (98870). However, the clinical validity of this analysis is limited because it did not evaluate the effect of soy-only phytoestrogens. Soy protein has also been compared with whey protein. One small clinical study in overweight and obese adults shows that patients taking soy protein isolate 52 grams for 23 weeks had similar overall weight and fat loss as those taking whey protein concentrate 52 grams daily (86077). In contrast, another small clinical study in overweight males shows that taking soy isolate 60 grams before lunch daily for 12 weeks is less effective for weight loss when compared with taking whey protein concentrate 65 grams (91801).
• Osteoarthritis. It is unclear if oral soy protein reduces osteoarthritis pain. Details: Preliminary clinical research shows that taking soy protein 40 grams daily for three months improves range of motion, pain, and quality of life in osteoarthritis patients, particularly males, when compared to baseline. However, these beneficial effects seem to also be observed following supplementation with milk-based protein, indicating that the benefits may have resulted from a placebo effect (75266).
• Overall mortality. It is unclear if dietary soy reduces overall mortality; the available research is conflicting. Details: A meta-analysis of observational studies has found that the highest intake of soy products is not associated with a lower risk of overall mortality, mortality from cardiovascular disease, or mortality from cancer when compared with the lowest intake (96941). However, a more recent population study has found that consuming at least 60 grams of soy daily over a 12-month period is associated with a 17% reduced risk of overall mortality over the next 5 years when compared with consuming less than 15 grams daily (108253). Also, an observational study in Japanese patients followed over 14.8 years has found that although overall soy intake is not associated with any benefit, increased intake of fermented soy products, such as natto and miso, was found to be associated with a slightly reduced risk of mortality (105600).
• Polycystic ovary syndrome (PCOS). It is unclear if oral soy reduces PCOS symptoms. Details: Clinical research shows that taking soy isoflavones 50 mg daily for 12 weeks improves insulin levels and insulin resistance by a small amount when compared with placebo in patients with PCOS. Furthermore, taking soy isoflavones improves the free androgen index by approximately 25% and triglyceride levels by 14% when compared to baseline. However, taking soy isoflavones does not improve low- or high-density lipoprotein (LDL or HDL) cholesterol levels or markers of inflammation (95994).
• Postmenopausal conditions. It is unclear if oral soy is beneficial for postmenopausal conditions. Details: A meta-analysis of generally small clinical trials in postmenopausal adults shows that taking soy protein with isoflavones or soy isoflavones, usually for 3-24 months, has modest beneficial effects on total cholesterol, and possibly high-density lipoprotein (HDL) cholesterol, when compared with milk protein, soy protein without isoflavones, or placebo. However, there was no effect on low-density lipoprotein (LDL) cholesterol or triglyceride levels. Subgroup analyses show that reductions in LDL cholesterol levels occur when soy is used for less than 6 months, in individuals older than 55 years, and when the soy protein contains isoflavones (108249).
• Preterm labor. It is unclear if oral soy reduces the risk for preterm labor. Details: Clinical research in patients with gestational diabetes shows that consuming a diet containing soy protein along with other plant and animal proteins for 6 weeks, beginning at 24-28 weeks' gestation, does not reduce the likelihood for caesarean section, preterm delivery, or maternal hospitalization when compared with a control diet containing only non-soy plant and animal proteins (95993).
• Premenstrual syndrome (PMS). It is unclear if oral soy reduces PMS symptoms. Details: Preliminary clinical research in patients with PMS shows that taking isolated soy protein containing soy isoflavones 68 mg daily for two menstrual cycles reduces cramps and swelling when compared with placebo (75279).
• Prostate cancer. It is unclear if oral soy is beneficial for the treatment or prevention of prostate cancer; research is conflicting. Details: Observational and clinical research has evaluated the effects of soy intake on prostate cancer risk. Observational research has found that consuming an Asian diet, which contains 10 times more soy than the average American diet, is associated with a lower risk of prostate cancer; however, it is unclear whether it is the soy content of the diet or if genetic differences or environmental factors such as fat ingestion are responsible for this correlation (2298,12884,12886,12887). A meta-analysis of observational trials from North America, Europe, and Asia has found that highest intake of total soy foods, unfermented soy foods, or soy isoflavones is associated with a reduced risk of prostate cancer when compared with the lowest intakes. However, higher intake of fermented soy foods is not associated with a reduced risk (96939). Furthermore, some observational research in Japanese males has found a weak association between increased prostate cancer mortality and a higher dietary intake of soy isoflavones when compared with a lower intake (105607). Research evaluating the use of soy supplements is also conflicting. One clinical study shows that taking soy protein 40 grams daily for 6 months reduces the development of prostate cancer six-fold in those at risk of prostate cancer when compared with milk protein (75432). However, another clinical study in healthy adults aged 50-80 years shows that taking soy protein, providing 83 mg isoflavones, daily for a year does not affect PSA levels when compared with a soy protein drink without isoflavones (12888). Soy products have also been evaluated in patients with prostate cancer. One clinical study shows that consuming a specific bread containing 50 grams of soy, providing 117 mg isoflavones, reduces PSA levels after about 3 weeks of treatment when compared with control (13140). Other preliminary clinical research in patients with rising PSA levels following prior therapy for prostate cancer shows that consuming 8 ounces of soy milk, standardized to contain 47 mg isoflavones, three times daily for 12 months slows the increase in PSA levels from 56% to 20% when compared with baseline (75435). However, one clinical study shows that taking soy protein 40 grams daily for 6 months does not reduce prostate size or improve PSA levels in those diagnosed with prostate cancer when compared with milk protein (75432). Also, in those with early stage prostate cancer, consuming a soy beverage daily providing genistein 60 mg does not seem to affect risk factors for progression of prostate cancer, including testosterone, estradiol, PSA, and sex hormone binding globulin (SHBG) levels (11033). Furthermore, consuming soy protein isolate 20 grams standardized to contain approximately 70 mg isoflavones daily for two years does not prevent prostate cancer recurrence following radical prostatectomy when compared with placebo (90953). Reasons for the discrepancies are not entirely clear, but may include the relatively short trial durations (up to 12 months) and heterogeneity of soy preparations and dosing regimens.
• Rheumatoid arthritis (RA). It is unclear if oral soy reduces RA symptoms. Details: Preliminary clinical research in patients with RA shows that consuming a liquid diet containing hydrolyzed soy protein (Top Up) daily for 4 weeks does not improve pain intensity, morning stiffness, or joint swelling and tenderness when compared to consuming a normal daily diet (75619).
• Sarcopenia. It is unclear if oral soy reduces age-related muscle loss; evidence is conflicting. Details: Some clinical research in postmenopausal adults shows that consuming soy protein containing isoflavones 99 mg daily for 12 months does not improve hand grip strength or physical performance when compared with a milk protein placebo (75283). However, another small clinical study in older adults with low muscle mass living in China shows that taking soy, or a whey-soy blended protein, 16 grams daily for 6 months, slightly attenuates muscle loss when compared with no intervention (105603).
• Stroke. It is unclear if oral soy improves outcomes and overall function in people who have had a stroke. Details: One small clinical study shows that older adults with a history of stroke who consumed soy milk 500 mL daily while participating in a rehabilitation program had greater improvements in hand grip strength, 8-feet walking speed, walking performance, and 6-minute walk test after 8 weeks when compared with placebo. However, consuming soy milk did not lead to greater improvements in lean mass or overall short physical performance battery (SPPB) scores when compared with placebo (100321).
• Thyroid cancer. It is unclear if dietary soy reduces the risk for thyroid cancer. Details: Epidemiological research has found that high dietary intake of soy is associated with a reduced risk of thyroid cancer when compared with lower intake (7662,12041).
• Vaginal atrophy. It is unclear if topical soy improves vaginal atrophy. Details: A small clinical study in postmenopausal adults with vaginal atrophy shows that applying one gram of soy extract 4% vaginal gel daily for 12 weeks reduces vaginal dryness and pain during sexual intercourse and improves vaginal endometrial thickness when compared with placebo (90964).
• Wrinkled skin. Small studies suggest that oral and topical soy might reduce wrinkles. Details: A small clinical study in middle-aged females shows that consuming soy isoflavone 40 mg daily for 12 weeks improves skin elasticity and the appearance of fine wrinkles when compared with placebo (75388). Another small clinical study in females with photodamaged skin shows that applying a soy moisturizer containing soybean trypsin inhibitor and Bowman-Birk protease inhibitor (Aveeno Positively Radiant Daily Moisturizer, Johnson & Johnson CCI) twice daily for 12 weeks improves skin pigmentation, fine lines, texture, tone, and appearance when compared with a placebo moisturizer (75410). More evidence is needed to rate soy for these uses.

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LIKELY SAFE ...when safflower oil is used orally as part of the diet (6,13146,72238).

POSSIBLY SAFE ...when safflower oil is used topically for up to 8 weeks (95938). ...when safflower oil is administered intravenously in recommended doses by a health care professional. A specific safflower oil emulsion (Liposyn) 10% to 20% has been used intravenously for up to 2 weeks (72300,72301). ...when safflower yellow, a component of safflower flower, is administered intravenously and appropriately. Safflower yellow has been used with apparent safety in doses up to 150 mg daily for up to 5 weeks (94038,94041,102381).

CHILDREN: POSSIBLY SAFE
when safflower oil is administered intravenously in recommended doses by a healthcare professional. A specific safflower oil emulsion (Liposyn) 20% has been used intravenously in infants and children for up to 2 weeks (72284,72295). ...when safflower oil is used orally in medicinal amounts. Safflower oil 2.5 mL daily has been taken safely for 8 weeks (94042). There is insufficient reliable information available about the safety of safflower flower in children.

PREGNANCY: LIKELY SAFE
when safflower oil is used orally as part of the diet (6,13146,72238).

PREGNANCY: POSSIBLY SAFE
when safflower oil is administered intravenously in recommended doses by a healthcare professional (20529).

PREGNANCY: LIKELY UNSAFE
when safflower flower is used due to its abortifacient, menstrual stimulant, and uterine stimulant effects (11,12).

LACTATION: LIKELY SAFE
when safflower oil is used orally as part of the diet (6,13146,72238). There is insufficient reliable information available about the safety of safflower flower during lactation; avoid using.

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LIKELY SAFE ...when soy protein is used orally and appropriately. Soy protein products in doses up to 60 grams, providing up to 185 mg isoflavones, daily have been safely used in studies lasting up to 16 weeks (842,2293,2294,2296,3025,3402,3977,4755,6412,8530)(10372,11805).

POSSIBLY SAFE ...when soy extracts are used orally and appropriately, short-term. Soy extracts containing concentrated isoflavones in doses of 35-120 mg daily have been used with apparent safety for up to 6 months (4751,6455,7802,12040,12048,13209,95994,95999).

CHILDREN: LIKELY SAFE
when consumed in amounts commonly found in foods or as a component of infant formula (3400,4912,7331). Soy milk that's not designed for infants should not be used as a substitute for infant formula. Regular soy milk can lead to nutrient deficiencies (12045). Most evidence shows that exposure to soy formula or other soy products in infancy does not cause early onset of puberty or health or reproductive problems later in life (7331,11080,108245). However, some small cohort studies have suggested that higher soy intake during childhood may be associated with an increased risk of precocious puberty (108240) and may be weakly correlated with the development of breasts in children less than 2 years of age (75520). This is in contrast to an observational study in Chinese children ages 7-9 years which suggests that higher soy intake is associated with delayed puberty (108252). One small cohort study has also found that use of soy infant formula may be associated with an increased risk of endometriosis in adulthood, although endometriosis was also correlated with prematurity, which may have confounded the findings (101803).

CHILDREN: POSSIBLY UNSAFE
when used orally as an alternative to cow's milk in children with severe milk allergy (75359). Although soy protein-based infant formulas are often promoted for children with milk allergy, children with a severe allergy to cow's milk are also frequently sensitive to soy protein (9883). There is insufficient reliable information available about the safety of soy products when used in amounts higher than typical food quantities for children.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods (4912).

PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts. Soy contains mildly estrogenic constituents (3373,3988,3989,3990,3994,6029,75303). Theoretically, therapeutic use of soy might adversely affect fetal development; avoid using.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (4912). A single 20-gram dose of roasted soybeans, containing 37 mg isoflavones, produces four to six times less isoflavones in breast milk than provided in a soy-based infant formula (2290). There is insufficient reliable information available about the safety of long-term use of therapeutic amounts of soy during lactation.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B High doses of safflower oil might increase the risk of bleeding when taken with anticoagulant or antiplatelet drugs.  Details Small clinical studies show that taking safflower oil, approximately 55 grams daily for 2-3 weeks, decreases platelet aggregation (72241,72303). However, taking lower doses of safflower oil, such as 5 grams daily for 4 weeks, does not seem to affect platelet function (66267). In one case report, a 74-year-old male stabilized on warfarin developed urinary tract bleeding and an elevated INR after taking a safflower extract 20 grams daily for 14 days (95939).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, safflower oil might alter the effects of antidiabetes drugs.  Details Some clinical research shows that taking safflower oil 10 grams daily for 3 weeks can increase fasting blood glucose in patients with type 2 diabetes (13146). However, clinical research in patients with metabolic syndrome with or without impaired glucose tolerance shows that taking safflower oil 8 grams daily for 12 weeks reduces fasting glucose levels by around 8 mg/dL (108889). Some clinical research also shows that taking safflower oil 8 grams daily for 16 weeks does not affect fasting glucose levels in patients with type 2 diabetes (94039).

WARFARIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, safflower oil might increase the risk of bleeding when taken with warfarin.  Details In one case report, a 74-year-old male stabilized on warfarin developed urinary tract bleeding and an elevated INR after taking a safflower extract 20 grams daily for 14 days (95939).

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ANTIBIOTIC DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, antibiotics may decrease the activity of soy isoflavones.  Details Intestinal bacteria are responsible in part for converting soy isoflavones into their active forms. Antibiotics may decrease the amount of intestinal bacteria and decrease its ability to convert isoflavones (7657).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Soy can lower blood glucose and have additive effects with antidiabetes drugs.  Details Clinical research shows that whole soy diets and soy-based meals reduce fasting glucose levels in diabetic and non-diabetic individuals (75268,75296,75378,75493,96001). Also, individuals following a soy-based meal replacement plan seem to require lower doses of sulfonylureas and metformin to manage blood glucose levels when compared with individuals following a diet plan recommended by the American Diabetes Association (75268).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically soy protein may have additive effects with antihypertensive drugs and increase the risk of hypotension.  Details Although some contradictory research exists (14254), most clinical evidence suggests that consuming soy protein modestly reduces systolic and diastolic blood pressure in individuals with prehypertension or hypertension (13139,75482).

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, soy might reduce the clearance of caffeine.  Details Soy contains genistein. Taking genistein 1 gram daily for 14 days seems to inhibit caffeine clearance and metabolism in healthy females (23582). This effect has been attributed to inhibition of the cytochrome P450 1A2 (CYP1A2) enzyme, which is involved in caffeine metabolism. It is unclear if this effect occurs with the lower amounts of genistein found in soy.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Soy might modestly induce CYP2C9 enzymes. However, this effect does not seem to be clinically significant.  Details In vitro research suggests that an unhydrolyzed soy extract might induce CYP2C9. However, the significance of this interaction is likely minimal. In healthy females taking a specific extract of soy (Genistein Soy Complex, Source Naturals), blood levels of losartan, a CYP2C9 substrate, were not significantly affected (16825).

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, soy might have additive effects when used with diuretic drugs.  Details Animal research suggests that genistein, a soy isoflavone, increases diuresis within 6 hours of subcutaneous administration in rats. The effects seem to be similar to those of furosemide (75604). This effect has not been reported in humans.

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, soy might competitively inhibit the effects of estrogen replacement therapy.  Details Soy contains phytoestrogens and has been shown to have estrogenic activity in some patients (3860). Although this has not been demonstrated in humans, theoretically, concomitant use of soy with estrogen replacement therapy might reduce the effects of the estrogen replacement therapy.

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Soy products might reduce the absorption of levothyroxine in some patients.  Details Preliminary clinical research and a case report suggest that soy-based formulas inhibit the absorption of levothyroxine in infants with congenital hypothyroidism (20636,20637,75548,90959). A levothyroxine dosage increase may be needed for infants with congenital hypothyroidism while using soy-based formulas, and the dose may need to be reduced when soy-based formulas are no longer administered. However, in postmenopausal adults, clinical research shows that taking a single dose of soy extract containing isoflavones 60 mg along with levothyroxine does not affect the oral bioavailability of levothyroxine (95996).

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = C Taking soy products containing high amounts of tyramine along with MAOIs can increase the risk of hypertensive crisis.  Details Fermented soy products such as tofu and soy sauce contain tyramine, a naturally occurring chemical that affects blood pressure regulation. The metabolism of tyramine is decreased by MAOIs. Consuming more than 6 mg of tyramine while taking an MAOI can increase the risk of hypertensive crisis (15649). The amount of tyramine in fermented soy products is usually less than 0.6 mg per serving; however, there can be significant variation depending on the specific product used, storage conditions, and length of storage. Storing one brand of tofu for a week can increase tyramine content from 0.23 mg to 4.8 mg per serving (15649,15701,15702). Advise patients taking MAOIs to avoid fermented soy products that contain high amounts of tyramine.

PROGESTERONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = A Theoretically, combining soy isoflavones with transdermal progesterone may worsen bone density.  Details Clinical research suggests that significant bone loss may occur in females with osteoporosis who receive a combination of transdermal progesterone with soy milk containing isoflavones when compared with placebo, soy milk alone, or progesterone alone (69859).

TAMOXIFEN (Nolvadex) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, estrogenic soy isoflavones might alter the effects of tamoxifen.  Details Laboratory research suggests that genistein and daidzen, isoflavones from soy, can antagonize the antitumor effects of tamoxifen under some circumstances (7072,14362,8966); however, soy isoflavones might have different effects when used at different doses. A relatively low in vitro concentration of soy isoflavones such as 1 microM/L seems to interfere with tamoxifen, whereas high in vitro concentrations such as those >10 microM/L might actually enhance tamoxifen effects. People on a high-soy diet have soy isoflavones levels ranging from 0.1-6 microM/L. Until more is known, advise patients taking tamoxifen to avoid therapeutic use of soy products.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, soy might interfere with the effects of warfarin.  Details Soy milk has been reported to decrease the international normalized ratio (INR) in a patient taking warfarin. The mechanism of this interaction is not known (9672). However, animal and in vitro research suggests that soy may also inhibit platelet aggregation (3992). Dosing adjustments for warfarin may be necessary.

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General ...Orally and intravenously, safflower oil seems to be well tolerated.
Serious Adverse Effects (Rare):
Orally: Liver failure.

Dermatologic ...Intravenously, safflower yellow, a constituent of safflower flower, can cause skin rash (94038,94041). In one case, adjusting the rate of the drip improved the rash (94041).

Hepatic ...Orally, safflower oil has been associated with liver failure. There are at least 7 case reports of acute liver failure requiring liver transplant that are probably associated with over-use of safflower oil, usually for weight loss purposes. However, it is not clear what dose or duration of safflower use led to liver failure in these cases (99138).

Immunologic ...Safflower can cause an allergic reaction in individuals sensitive to the Asteraceae/Compositae family. Members of this family include ragweed, chrysanthemums, marigolds, daisies, and many other herbs.

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General ...Orally, soy is well tolerated.
Most Common Adverse Effects:
Orally: Bloating, constipation, diarrhea, and nausea.
All ROAs: Allergic reactions.

Endocrine ...In the 1950s and 1960s, cases of altered thyroid function, particularly goiter, were reported in children taking soy formula. However, adding iodine to soy formula or replacing soy flour in formula with soy protein isolate has nearly eliminated the risk of altered thyroid function in most infants (75353,75651).
In adults, there is some evidence that soy intake can alter thyroid function. Results from one clinical trial suggests that consuming soybeans 30 grams daily for as little as one month can increase thyroid-stimulating hormone (TSH) and decrease thyroxine, causing diffuse goiters, constipation, fatigue, and lethargy in some Japanese men. Recovery was achieved by discontinuing soybean intake (75206,75353). There is also some evidence that soy inhibits thyroid hormone synthesis resulting in increased secretion of TSH in some postmenopausal patients (7806). However, this seems to only occur in people with iodine deficiency (6466,75311). In postmenopausal patients with normal levels of iodine, taking a soy extract for 6 months does not seem to significantly affect thyroid hormone levels (13010).
Evidence from a single case-control study suggests that consumption of soy-based formulas may be associated with an observed three-fold increase in the risk of breast development in Puerto Rican children less than 2 years-old (75520). The correlation has been attributed to the estrogenic activity of soy. However, other risk factors, including a maternal history of ovarian cysts and consumption of meat products were also associated with the increased risk of breast development prior to 2 years of age. Also, the investigators noted that in over half of the cases, the child had not been exposed to soy or any of the other risk factors. Therefore, factors other than soy consumption may be more strongly associated with the increased risk of breast development prior to 2 years of age.

Gastrointestinal ...Gastrointestinal upset, such as constipation, diarrhea, bloating, and nausea are the most common side effects of soy (2297,11033,11082,15851,75491,95999). Reports of "bad taste" and taste intolerance have also been documented in clinical research (15851,39007,75491). Firmer stools, diarrhea, colitis, and intestinal mucosal damage has been reported in infants fed soy protein formula (75161,75448,75516,75525).

Genitourinary ...Orally, soy might increase discomfort during menstrual periods. Evidence from a small, retrospective cohort study has found that consuming soy formula as an infant may slightly increase the duration and discomfort of menstrual periods later in life. However, the investigators noted that these differences may not be clinically significant (7331).
Orally, frequent soy consumption might be a risk factor for uterine leiomyoma, an estrogen-dependent benign tumor located on the uterus. Observational research found that consumption of soy milk or soybean at least four times weekly is associated with a 7-fold increased odds of uterine leiomyoma (98869).
There is some concern that use of soy-based formulas in infants might result in long-term health complications. However, results from a retrospective cohort study has found that intake of soy-based formula as an infant does not affect height, weight, body mass index, pubertal maturation, menstrual history, or pregnancy history, nor does it increase the risk of reproductive organ disorders, hormonal disorders, libido dysfunction, or birth defects in the offspring of adults who received soy formula as infants (7331,11080). Additionally, research in adults shows that urinary phytoestrogens are not associated with endometriosis risk (101804). However, some population research has found that regular exposure to soy-based formulas during infancy is associated with an increased risk for endometriosis (101803).

Immunologic ...Orally, soy can cause allergic reactions such as skin rash and itching in some people (6412). In an 11-year-old female, allergy to soy protein resulting in a delayed itching papular rash was thought to be responsible for the reaction to injected benzathine benzylpenicillin containing possible soy protein-contaminated soy lecithin (96422).
Topically, soy-based ingredients were responsible for the development of hand atopic dermatitis in a young female using cosmetic lotions in the workplace. Percutaneous sensitization resulted in the development of anaphylaxis to oral soy (96000).

Neurologic/CNS ...Orally, one clinical study showed that insomnia was more common in postmenopausal adults taking soy isoflavone supplements when compared with those receiving placebo (9917). Some research suggests that dietary consumption of tofu during midlife might decrease cognitive function in later years. Evidence from one retrospective cohort study suggests that males who consume at least two servings of tofu weekly during midlife have increased risk of cognitive impairment in late life (19% vs. 4%) compared to those who consume tofu less frequently. Although the effect of tofu was considered to be marginal compared to other factors such as age, education, or history of stroke, results from the study suggest that the effect of significant midlife consumption of tofu is comparable to the effect of an age difference of 4 years or an education difference of 3 years. However, numerous other factors, such as lifestyle and health, could be involved (6415,6416). Therefore, these findings are too preliminary to be used as a basis for clinical recommendations.

Oncologic ...There is controversy about the role of soy in breast cancer. Population studies suggest that soy is protective against breast cancer. Asian females who eat a traditional diet high in soy seem to have a lower risk of developing breast cancer (4590,5939,9674). Early exploratory studies have suggested that soy stimulates proliferation of normal human breast tissue (3980,3981). However, taking a soy tablet containing 50 mg soy isoflavones daily for 12 months does not alter mammographic or breast MRI tissue density in adults at high risk of breast cancer, with non-endocrine treated breast cancer, or previously treated for breast cancer and without evidence of recurrence (95999).
There is some concern that soy supplements, but not soy foods, might increase the risk of endometrial hyperplasia due to its estrogenic effects. Population and clinical research suggests that soy foods do not have a proliferative effect on endometrial cells (7358,2429,7654,9676,9917), and increased dietary soy and phytoestrogens are associated with reduced endometrial cancer risk (7338,10372). However, the effects seem to be different with concentrated soy isoflavone extract. While taking products providing isoflavones 120 mg daily for 6 months does not increase endometrial thickening (13209), taking higher doses such as isoflavones 150 mg daily for 5 years might increase the risk of simple endometrial hyperplasia (12105). However, there is no evidence that soy isoflavones increase the risk of atypical hyperplasia which has a much higher risk of developing into endometrial cancer than simple endometrial hyperplasia (12105,90973).
There is also concern that increased soy intake increases the risk for other types of cancer. Some observational research has found that higher dietary intake of soy is associated with a higher risk for bladder cancer and pancreatic cancer (9677,105609).
A meta-analysis of results from cohort and case-control studies evaluating the risk of stomach cancer related to consumption of fermented soy products is unclear and inconclusive. The highest quality data from cohort studies suggests that these products have no significant effect on stomach cancer (7340,7341). More research is required to determine if soy products have any correlation with stomach cancer.

Pulmonary/Respiratory ...Inhaled soy dust and soy hull aeroallergen can trigger symptoms of asthma and allergic rhinitis (5084,5085,5086).

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