JuiceFestiv - Daily Veggie by Natrol

Coronary heart disease (CHD). Consuming barley 3-3.6 grams daily as a source of dietary fiber appears to reduce the risk of CHD. Details: Clinical research shows that a diet containing foods high in soluble fiber, such as whole grain barley or dry milled barley, reduces the risk of heart disease (2737,4962,4963,4964,4965,4966,4967,4968). In 1993, the US Food and Drug Administration (FDA) approved a health claim stating that consuming at least 3 grams of soluble fiber per day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of CHD (5792,5797,102336). However, some clinical research shows that at least 3.6 grams of soluble fiber daily is needed to reduce the risk of CHD (5788,5795).
Hypercholesterolemia. Consuming barley 3-12 grams daily seems to reduce total cholesterol and low-density lipoprotein (LDL) cholesterol levels in adults with hypercholesterolemia. Details: Clinical research shows that taking barley significantly reduces total cholesterol and low-density lipoprotein (LDL) cholesterol when used with a normal diet or added to the National Cholesterol Education Program's Step I diet (11134,11986,17129,33734,33748,33752). A meta-analysis of 11 clinical trials shows that consuming preparations containing barley 3-12 grams daily for at least 4-12 weeks reduces total cholesterol and LDL cholesterol levels by around 12 mg/dL and 10 mg/dL, respectively, with no change in triglyceride or high-density lipoprotein (HDL) cholesterol levels. These changes did not appear to be dose-dependent (17129). However, a small clinical study in males with hypercholesterolemia shows that the effect of barley on cholesterol is modestly dose-dependent. Taking 0.4 grams, 3 grams, or 6 grams of soluble fiber from barley daily for 5 weeks reduces total cholesterol by 14%, 17%, and 20%, respectively, and reduces LDL cholesterol by 17%, 17%, and 24%, respectively, when compared to baseline (11986). The form of barley used may alter its effect on cholesterol levels. Some research has shown that barley highly enriched (75% by weight) with beta-glucans does not seem to significantly affect cholesterol. This lack of effect seems to be the result of processing the barley into a highly enriched beta-glucans product (10166). Food processing seems to affect beta-glucans structure or solubility and therefore decreases the cholesterol lowering effects of barley.

Colorectal cancer. Increased consumption of barley as a source of fiber does not appear to be beneficial for primary or secondary prevention of colorectal cancer. Details: Clinical and observational research shows that consuming dietary cereal fiber, including barley fiber, does not reduce the risk of colorectal cancer or prevent colorectal cancer recurrence (160,4819,4820,4821,5104).

Coronavirus disease 2019 (COVID-19). It is unclear if oral barley is beneficial in patients with COVID-19. Details: A small clinical study in Iranian adults hospitalized with moderate COVID-19 shows that drinking 250 mL of Persian barley water daily for 2 weeks, along with conventional treatment, decreases length of hospital stay, body temperature, and markers of inflammation when compared with conventional treatment alone. However, Persian barley water does not appear to improve oxygen saturation or symptoms of COVID-19 (111148). The validity of these findings is limited by a lack of placebo control and concerns related to the statistical methods used.
Diabetes. Although there has been interest in using oral barley for diabetes, there is insufficient reliable information about the clinical effects of barley for this purpose.
Diarrhea. Although there has been interest in using oral barley for diarrhea, there is insufficient reliable information about the clinical effects of barley for this purpose.
Gastric cancer. It is unclear if oral barley is effective for the prevention of gastric cancer. Details: Observational research suggests that increased consumption of dietary fiber, a component of barley, is associated with 70% lower odds of gastric cancer when compared with low consumption of dietary fiber (10435).
Gastritis. Although there has been interest in using oral barley for gastritis, there is insufficient reliable information about the clinical effects of barley for this purpose.
Hypertension. Although there has been interest in using oral barley for hypertension, there is insufficient reliable information about the clinical effects of barley for this purpose.
Obesity. Although there has been interest in using oral barley for obesity, there is insufficient reliable information about the clinical effects of barley for this purpose.
Ulcerative colitis. Small clinical studies suggest that oral barley might improve symptoms associated with ulcerative colitis. Details: Several small, open-label trials in patients with ulcerative colitis show that consuming food containing germinated barley 20-30 grams daily for 4-24 weeks reduces symptoms of ulcerative colitis when compared to baseline (33725,33729,33732,33777). However, the validity of these findings is limited by a lack of comparator groups. Barley has also been studied in combination with other ingredients. A small clinical study in adults with mild to moderate ulcerative colitis shows that taking a specific nutritional supplement (Profermin, Nordisk Rebalance) containing barley malt flour, oat flour, Lactobacillus plantarum, and lecithin twice daily for 8 weeks decreases symptom scores by at least 50% in an additional 26% of patients when compared with a control nutritional supplement. Disease remission occurred in 31% of patients taking this product compared with 15% of patients in the control group (92818). It is unclear if these findings are due to barley, other ingredients, or the combination. More evidence is needed to rate barley for these uses.

Athletic performance. Oral beet may improve athletic performance associated with aerobic activities. However, it is not clear who is most likely to benefit, for which type of competition it is most useful, or what dose or duration of use is most appropriate. Details: Several small clinical trials, most of which enrolled males only, as well as a meta-analysis of some of these studies, show that beet improves various measures of athletic performance. Conversely, another meta-analysis of several small clinical studies, that includes some of these studies, shows that taking beetroot does not improve performance in high-intensity or sprint interval training (111159). The most commonly used doses in all studies, regardless of effect, have included an acute dose of beetroot juice 70-500 mL up to 3 hours prior to exercise (93844,94463,94464,94466,94467,94473,97726,100142,100143,105761)(105762,111159) or chronic dosing of up to 500 mL daily for 3-6 days (94459,94464,94469,100145,100147,100153,111159). Less commonly, beetroot juice 70-140 mL daily, betalain-rich concentrate 100 mg daily, or a beetroot-based nutritional gel 100 grams daily, have been taken for longer dosing schedules of 7-15 days (97720,100144,100148,100152,105763). Brands of juice used in clinical trials have included Beet It Sport (James White Drinks Ltd.) (94455,94458,94465,100142,100143,100144,100148,105761,105763), Beet It Stamina Shot (James White Drinks Ltd.) (93844), Beet It (James White Drinks Ltd) (94457,94459,94460,94467,94469,97726,100145,100153,105762,111159), and Love Beets Beetroot Juice (Gs Fresh Ltd.) (94461,94462). Although plasma levels have not been analyzed in all studies, the majority of studies suggest that these doses are adequate to increase levels of nitrates or nitrites, which is thought to be essential for increasing athletic potential (93844,94455,94458,94459,94460,94465,94467,94469,94466,94473,97726). The evidence also suggests benefit in both normoxic and hypoxic environments (94465,100148,105763). Research in recreationally-trained athletes or sedentary individuals has shown some benefit. Clinical research shows beetroot juice improves the use of oxygen during exercise testing in recreationally-trained athletes, especially with severe exercise testing (94460,94463,94467,100147,105762). There is also some evidence of improvement in ability or strength (93844,94464,94468,100143,100150,100152). Also, in obese adolescents, taking beetroot juice daily for 6 days increases the time to exhaustion from severe exercise, but does not improve moderate exercise (100145). However, results are not consistent even within the same publication, suggesting that some differences might be related only to chance. By contrast, the majority of research in elite athletes does not support the use of beetroot juice to decrease the time needed to complete a task, aid in some sort of graded exercise test, or improve the use of oxygen during exercise testing (94455,94458,94460,94461,94464,94465,94466,94469,94473,100142,100153,105763). However, some research does suggest that specific sprint sets might be improved (94469) and that beet may improve power output and anaerobic capacity during morning workouts (105761). Also, higher doses or a longer duration might be necessary to improve the time to complete a running or cycling trial. Benefits in elite athletes, most often related to time trials, are usually limited to studies using chronic dosing of 7-15 days, which is longer than the duration of 6 days used in the majority of studies (94473,97720,100144,100148). The supposed lack of effect of beetroot juice in elite athletes might be related to the natural production of nitrates and nitrites in the body or the increased ability to use oxygen that comes from extensive training (94458,94463). Alternatively, any changes might be very small (<1%) and not identified with statistical comparisons, although even very small changes might be beneficial in competition (94464).
Exercise-induced muscle soreness. Drinking beetroot juice 7-8 times over 48 hours after strenuous exercise may reduce exercise-induced muscle soreness. Details: Some clinical research shows drinking beetroot juice (Love Beets Beetroot Juice, Gs Fresh Ltd.) 125 mL or 250 mL seven times over 48 hours after strenuous box jumps improves muscle soreness when compared with placebo and sodium nitrite (96964,97722). Also, a small clinical study shows that drinking beetroot juice 250 mL as eight separate doses over 48 hours after a repeated sprint test improves muscle soreness when compared with placebo (94461). However, drinking this same beetroot juice 250 mL as seven separate doses over 48 hours after running a marathon does not appear to reduce muscle soreness when compared with placebo (94462). These studies were also included in a meta-analysis along with 2 other small studies. This analysis of mostly healthy or physically active males shows that drinking beetroot juice improves the pressure pain threshold, which is a measure of muscle soreness, at 48- and 72-hours post-exercise when compared with a fruit-flavored drink. However, beetroot juice does not improve subjective muscle soreness scores (111160). The validity of the findings from this meta-analysis is limited by the heterogeneity of the beetroot juice regimens among the included studies. Further, these results should not be generalized to elite athletes.

Chronic obstructive pulmonary disease (COPD). Drinking beetroot juice for up to 14 days may not improve exercise capacity in patients with COPD. Details: A meta-analysis of eight small clinical trials in patients with COPD shows that taking nitrate-rich beetroot juice does not improve most measures of exercise capacity, including the 6-minute walk test, cycling ergometry endurance time, and maximum rate of oxygen consumption (VO2 max), when compared with placebo. Additionally, beetroot juice did not reduce blood pressure or heart rate. However, the analysis did show a significant improvement in scores on the Borg Rating of Perceived Exhaustion scale with beetroot juice over placebo. Nitrate-rich beetroot juice doses ranged from 70-140 mL daily for up to 14 days (104200).

Cognitive function. It is unclear if drinking beetroot juice is beneficial for cognitive function. Details: A small clinical study in adults with overweight or obesity on a calorie-restricted diet shows that drinking 70 mL of concentrated beetroot juice daily for 14 days improves the time to complete part B of the trail making test, which is a test of cognitive function, but not part A, when compared with controls (111158). However, the duration and size of this study limits its validity. Further, it is unclear whether any improvement is clinically significant.
Coronary heart disease (CHD). It is unclear if oral beetroot extract is beneficial in patients with CHD. Details: A small clinical trial in patients with CHD shows that taking red beetroot extract 500 mg, containing around 25 mg betalains, twice daily for 2 weeks reduces total cholesterol and low-density lipoprotein (LDL) cholesterol by 15 mg/dL and reduces triglycerides by 8 mg/dL when compared to baseline. Slight improvements in blood pressure and blood glucose were also reported, but these changes were not clinically significant (103883). The validity of these findings is limited by the lack of a comparator group. Also, it is unclear whether beetroot can reduce the risk of cardiovascular events in patients with CHD.
Dyslipidemia. It is unclear if oral beetroot is beneficial in patients with dyslipidemia. Details: A meta-analysis of small clinical studies in healthy individuals or patients with dyslipidemia, cardiovascular disease, or overweight or obesity, shows that consuming beetroot juice or leaves does not improve levels of triglycerides or total, low-density lipoprotein, or high-density lipoprotein cholesterol when compared with controls (111163). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the enrolled patients and beetroot regimens.
Exercise-induced muscle damage. It is unclear if oral beetroot juice improves recovery from muscle damage after exercise. Details: A meta-analysis of 4 small clinical studies in healthy or physically active individuals, most of which enrolled males only, shows that drinking beetroot juice improves measures of muscle recovery at 72 hours post-exercise when compared with a fruit-flavored drink. However, beetroot juice does not consistently improve recovery at earlier time points post-exercise, nor does it reduce levels of creatine kinase or markers of inflammation (i.e., interleukin-6, interleukin-8, c-reactive protein, or tumor necrosis factor-alpha) (111160). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the beetroot juice regimens among the included studies, which usually varied from 210-250 mg of nitrate in 7-11 servings over 3-7 days. Further, these results should not be generalized to elite athletes.
Hypertension. Oral beet may slightly reduce blood pressure in healthy individuals, but it is unclear if it is beneficial in patients with hypertension. Details: Meta-analyses of small studies show the potential for a minor reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in healthy adults taking beetroot juice (94470,97718,97728). The average reduction in SBP and DBP with beetroot juice consumption is about 4 mmHg and 1 mmHg, respectively, which is greater than the effect seen with consuming blackcurrant juice or nitrate-depleted beetroot juice. The most benefit is seen when beetroot juice is taken for at least 2 weeks or at doses of 500 mL daily (97728). Another small clinical study shows that consuming beet 100 grams baked into bread modestly decreases DBP over a 6-hour period when compared with white bread (97725). It is possible that genetics might play a role in the magnitude of effect seen with beetroot consumption. Adults with a specific gene polymorphism, eNOS Glu298Asp, experienced a greater reduction in DBP after consuming beet-containing bread (97724). Despite positive findings in studies of healthy individuals, research on the use of beetroot juice in patients with hypertension is unclear. A small clinical study in adults with hypertension who were taking antihypertensive medications shows that drinking nitrate-rich beetroot juice (Beet it; James White Drinks Ltd.) 70 mL twice daily for one week does not lower blood pressure when compared with nitrate-depleted beetroot juice (94457). Also, in patients with mild to moderate hypertension, clinical research shows that taking a combination of beetroot powder (Sensient) 300 mg, olive leaf extract 1000 mg, and green coffee bean extract 200 mg daily for 6 weeks does not lower blood pressure when compared with placebo (97723). However, some evidence suggests that at least part of the blood pressure lowering effects of beet might be independent of nitrate (97728). Furthermore, some research suggests that identifying effects on blood pressure might be dependent on the method of measurement, including clinic resting measurements, 24-hour monitoring, or morning/evening home resting measurements (97729).
Hypertriglyceridemia. It is unclear if oral beet is beneficial in patients with hypertriglyceridemia. Details: A small clinical study in overweight or obese individuals with dyslipidemia shows that taking freeze-dried beet leaf 2.8 grams daily for 4 weeks in addition to nutritional guidance does not lower triglyceride levels when compared with nutritional guidance alone (100146). Beet has also been evaluated in combination with other ingredients. A small clinical trial in patients at risk for heart disease shows that a specific combination of beet and hawthorn berry (Neo40-Daily, Neogenis Labs), taken twice daily for 30 days, can modestly reduce blood triglyceride levels when compared to baseline (18222). It is unclear if these findings are due to beet, hawthorn berry, or the combination.
Liver disease. Although there has been interest in using oral beet for liver disease, there is insufficient reliable information about the clinical effects of beet for this purpose.
Muscle strength. It is unclear if oral beetroot juice is beneficial for muscle strength. Details: A small clinical study in adults with overweight or obesity on a calorie-restricted diet shows that drinking 70 mL of concentrated beetroot juice daily for 14 days improves handgrip strength by approximately 18% compared with 4% in controls (111158). However, it is unclear whether any improvement is clinically significant.
Obesity. It is unclear if oral beet leaf or beetroot juice is beneficial for weight loss. Details: A small clinical study in patients with overweight or obesity and dyslipidemia shows that taking freeze-dried beet leaf 2.8 grams daily for 4 weeks in addition to nutritional guidance does not reduce body weight or body mass index (BMI) when compared with nutritional guidance alone (100146). Similarly, a small clinical study in adults with overweight or obesity on a calorie-restricted diet shows that drinking 70 mL of concentrated beetroot juice daily for 14 days does not improve weight loss when compared with controls (111158). However, the size and duration of this study may have been inadequate to detect differences between groups.
Pregnancy-induced hypertension. It is unclear if oral beetroot juice is beneficial in patients with pregnancy-induced hypertension. Details: A small clinical trial in pregnant patients with hypertension who are at approximately 22-35 weeks gestation shows that taking beetroot juice (James White Drinks Ltd) 70 mL daily for 8 days does not reduce blood pressure when compared with a nitrate-depleted beetroot juice (100151). However, the study was small and designed to investigate the feasibility of using beetroot juice in this population.
Pulmonary hypertension. It is unclear if oral beetroot juice is beneficial in patients with pulmonary hypertension. Details: A small clinical study shows that taking beetroot juice (Beet-It Sport; James White Drinks Ltd) 70 mL twice daily for 7 days does not improve right ventricular systolic function when compared with nitrate-depleted beetroot juice in patients with pulmonary hypertension (100149). However, this study was small and not adequately powered to detect differences between groups.
Raynaud syndrome. It is unclear if oral beetroot juice is beneficial in patients with Raynaud syndrome. Details: A small clinical study in patients with Raynaud syndrome undergoing cold sensitivity tests shows that drinking beetroot juice (Beet-It, James White Drinks Ltd) 70 mL daily for 13 days, followed by 140 mL prior to testing, does not reduce pain in the hands or feet, but might improve thermal comfort in the feet, when compared to baseline (103884). The validity of this finding is limited by the lack of a comparator group. More evidence is needed to rate beet for these uses.

Hypertension. Oral blue-green algae seem to modestly reduce blood pressure in patients with hypertension. Details: Some small clinical studies show that blue-green algae can decrease blood pressure in patients with hypertension (97206,99654). A meta-analysis of five small clinical trials in patients with hypertension, type 2 diabetes, or chronic pain shows that taking spirulina blue-green algae 1-8 grams daily for up to 12 weeks reduces systolic blood pressure (SBP) by 5 mmHg and diastolic blood pressure (DBP) by 7 mmHg when compared with placebo. The effect size was larger in patients with hypertension and in those treated for at least 12 weeks (109964). Another small clinical study shows that taking spirulina blue-green algae (A. maxima) 4.5 grams daily for 6 weeks decreases blood pressure in adults with hypertension, with the number of subjects fulfilling the criteria for hypertension decreasing from 45% to 14% when compared to baseline (18297). A more recent clinical study in patients with hypertension shows that consuming a salad dressing containing 2 grams spirulina blue-green algae daily for 8 weeks reduces SBP by around 6 mmHg and DBP by around 4 mmHg when compared to baseline. While overall reduction in blood pressure with spirulina dressing was larger when compared with patients consuming a control dressing, the study groups were heterogenous at baseline, limiting the validity of any statistical comparisons between groups (109965).

Allergic rhinitis (hay fever). It is unclear if oral blue-green algae are beneficial in allergic rhinitis. Details: Preliminary clinical research shows that taking spirulina blue-green algae (A. platensis) 2 grams daily for 6 months, improves self-rated scores for sneezing, nasal discharge, nasal congestion, and itching when compared with placebo in adults with allergic rhinitis (18300).
Antiretroviral-induced insulin resistance. It is unclear if oral blue-green algae are beneficial for insulin resistance due to antiretrovirals. Details: Preliminary clinical research shows that taking spirulina blue-green algae (A. platensis) 19 grams daily for 2 months increases insulin sensitivity by about 225% when compared to baseline in patients with antiretroviral-induced insulin resistance (75944). The validity of this finding is limited by the lack of a comparator group.
Anxiety. Although there has been interest in using oral blue-green algae for anxiety, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
Arsenic poisoning. It is unclear if oral blue-green algae are beneficial for chronic arsenic toxicity. Details: Preliminary clinical research in people living in areas of Bangladesh with high arsenic levels in drinking water shows that taking a combination of an alcoholic extract of spirulina blue-green algae 250 mg and zinc 2 mg orally twice daily for 16 weeks, in addition to use of filtered drinking water, increases urinary arsenic excretion, reduces hair arsenic levels, and improves skin manifestations of chronic arsenic toxicity when compared with placebo plus filtered water (18301).
Athletic performance. Most research suggests that oral blue-green algae are not beneficial for improving athletic performance; however, the available studies are small. Details: AAlthough some research disagrees, most small or preliminary clinical trials show that taking spirulina blue-green algae does not improve athletic performance in trained or untrained adults. One study shows that, when compared with placebo, taking spirulina blue-green algae (Hawaiian Spirulina, Cyanotech Corporation) 3 grams daily for up to 8 weeks has no effect on exercise output during a 30-minute elliptical trainer workout in active males (97203). In elite rugby players, taking spirulina blue-green algae (Algae Green Value) 5.7 grams daily for 7 weeks does not improve jump or sprint performance or body composition when compared to placebo (104567). In healthy untrained males, a small study shows that taking spirulina blue green algae 6 grams daily for 7 days does not increase the time to fatigue related to arm cycling following a 30-minute submaximal exercise bout (104566). In male recreational runners, spirulina blue-green algae (A. platensis) 2 grams three times daily for 4 weeks was not associated with any change in exercise intensity during a 2-hour treadmill jogging period. However, sprinting time to exhaustion following the 2-hour jog increased from 2.05 minutes to 2.7 minutes (18306). Also, a study of athletes and non-athletes shows that taking spirulina blue-green algae (Parry Nutraceuticals) 2 grams daily for 8 weeks has a small effect on isometric muscle strength, but not muscle endurance, when compared with placebo (104568).
Attention deficit-hyperactivity disorder (ADHD). Oral blue-green algae have only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking 3 mL of a specific combination of spirulina blue-green algae, peony, ashwagandha, gotu kola, bacopa, and lemon balm (Nurture and Clarity, Tree of Healing-LD) diluted in 50-60 mL of water three times daily for 4 months improves ADHD scores when compared with placebo in previously untreated children aged 6-12 years (19272). It is unclear if this effect is due to blue-green algae, other ingredients, or the combination.
Beta-thalassemia. It is unclear if oral blue-green algae are beneficial in beta-thalassemia. Details: In children with beta-thalassemia, preliminary clinical research shows that taking spirulina blue-green algae (GNC Natural Brand Spirulina, General Nutrition Corporation) 250 mg/kg daily, up to a maximum dose of 4 grams daily, for 3 months reduces the percentage of children requiring blood transfusion during an interval of less than 2 weeks from 66% to 40%. There were also improvements in red blood cell count and levels of hemoglobin, ferritin, and liver function enzymes (104569). However, the validity of these findings is limited by the lack of a comparator group.
Blepharospasm. It is unclear if oral blue-green algae are beneficial when used in conjunction with botulinum toxin injections. Details: Preliminary clinical research shows that taking a specific product containing the blue-green algae species Aphanizomenon flos-aquae (Super Blue-Green Algae, Cell Tech) 1500 mg per day orally for 6 months in addition to botulinum toxin-A injections does not reduce eyelid spasms when compared with botulinum toxin-A alone in people with essential blepharospasm or Meige syndrome (14842).
Cancer. Although there has been interest in using oral blue-green algae for cancer, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
Cardiovascular disease (CVD). Although there has been interest in using oral blue-green algae for CVD, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
Cognitive Impairment. It is unclear if oral blue-green algae are effective for improving cognitive impairment. Details: A small clinical study in patients aged 60 or older with mild cognitive impairment shows that taking blue-green algae extract 1 gram 3 times daily for 12 weeks slightly improves some components of cognitive function testing related to visual learning, memory, and vocabulary when compared with placebo (112001). However, the validity of these findings is limited by lack of adjustment for multiple comparisons, which may explain the discrepant results with the other components of the cognitive function tests.
Depression. Although there has been interest in using oral blue-green algae for depression, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
Diabetes. It is unclear if oral blue-green algae are beneficial in diabetes. Details: A meta-analysis of seven small clinical studies in patients with type 2 diabetes shows that taking spirulina blue-green algae 0.8-14 grams daily for 6-12 weeks reduces fasting blood glucose and improves total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol, but does not affect low-density lipoprotein (LDL) cholesterol, when compared with placebo. There was no reduction in glycated hemoglobin (HbA1c); however, all but two of the studies lasted less than 12 weeks, limiting the validity of the findings related to HbA1c (109970).
Dyslipidemia. It is unclear if oral blue-green algae are beneficial in dyslipidemia. Details: Several clinical studies in patients with normal or elevated cholesterol levels show that doses of spirulina blue-green algae (A. platensis, A. maxima, A. fusiformis) ranging from 1-10 grams daily for 1-6 months may reduce total cholesterol by 8% to 27%, low-density lipoprotein (LDL) cholesterol by 10% to 65%, and triglycerides by 0% to 23%; and increase high-density lipoprotein (HDL) cholesterol by 0% to 66% (18297,18298,18299,91705,91708,91710,91717,102689). However, the validity of these studies is limited by methodological weaknesses and heterogeneous population characteristics. A meta-analysis of 23 small studies, several of which were in patients with type 2 diabetes or obesity, shows that taking blue-green algae 0.8-10 grams for 4 to 24 weeks modestly improves levels of LDL, HDL, triglycerides, and total cholesterol when compared with placebo or no treatment (112004). The interpretation of these findings is limited by the high heterogeneity of the included studies which enrolled patients of varying health status and employed various study designs.
Dyspepsia. Although there has been interest in using oral blue-green algae for dyspepsia, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
Exercise-induced muscle soreness. It is unclear if oral blue-green algae are effective for the prevention of exercise-induced muscle soreness. Details: A small clinical study in recreationally trained males shows that taking spirulina blue-green algae 2 grams three times daily does not reduce delayed onset muscle soreness after eccentric exercise when compared with placebo (109967).
Hepatitis C. Evidence for the use of oral blue-green algae in hepatitis C is conflicting. Details: One clinical study in adults with chronic hepatitis C who are unresponsive to interferon treatment shows that taking spirulina blue-green algae (A. platensis) 500 mg orally three times daily for 6 months is associated with greater improvements in alanine aminotransferase (ALT) levels than taking silymarin 140 mg three times daily. Complete virological response rates were 13% with blue-green algae and 3% with silymarin, although this difference was not statistically significant (63247). However, in another study in people with chronic hepatitis B or C, liver function enzyme levels worsened after one month of treatment with oral spirulina blue-green algae (18304).
HIV/AIDS. It is unclear if oral blue-green algae are beneficial for people with HIV/AIDS who do not have access to antiretrovirals. Details: One clinical study in adults with untreated HIV shows that taking spirulina blue-green algae (A. platensis) powder 5-10 grams daily for 3-6 months does not affect CD4 counts, viral load, or weight gain in patients with HIV (75927,91707). However, in one study, the incidence of opportunistic infections, respiratory disease, gastrointestinal symptoms, and fatigue was 43% for patients taking spirulina blue-green algae, compared to 70% for patients taking placebo (91707).
Iron deficiency anemia. Although there has been interest in using oral blue-green algae for iron deficiency anemia, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
Lichen planus. It is unclear if oral blue-green algae are beneficial in patients with oral lichen planus. Details: A small clinical study in patients with oral lichen planus shows that taking spirulina blue-green algae 500 mg twice daily for 8 weeks along with application of triamcinolone acetonide 0.1% oral paste three times daily for 1 week reduces pain and lesion size when compared with only triamcinolone acetonide three times daily for 8 weeks (109963).
Malnutrition. Evidence for the use of oral blue-green algae in malnutrition is conflicting. Details: Some clinical research in severely undernourished children shows that adding spirulina blue-green algae (A. platensis) 5 grams orally twice daily for 8 weeks to a traditional diet results in an average daily weight gain of 25 grams, compared with only 15 grams for those given the traditional diet alone. Similarly, giving blue-green algae 10 grams twice daily for 8 weeks in addition to a misola diet (millet, soy, peanut kernel, sugar, and salt) results in an average daily weight gain of 34 grams, compared with only 20 grams for children given the misola diet alone (18308). However, a small clinical study in malnourished children aged 3 months to 3 years shows that giving spirulina blue-green algae 5 grams daily for 3 months in addition to a traditional diet fails to increase weight gain more than the traditional diet alone (18309). Similarly, a moderate-size crossover study in preschool-aged children in Cambodia shows that taking blue-green algae 2 grams 5 times a week during the first hour of school for 8 weeks does not improve weight gain or height but may reduce the proportion of children with anemia when compared with placebo (112002). The interpretation of these findings is limited by the high rate of patients lost to follow-up and the lack of statistical adjustment for confounding factors, such as parasitism and home diet.
Memory. Although there has been interest in using oral blue-green algae for memory, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
Menopausal symptoms. It is unclear if oral blue-green algae are beneficial for improving symptoms of menopause. Details: A preliminary clinical study shows that taking a product containing the blue-green algae species Aphanizomenon flos-aquae (Klamin, Nutrigea) 1.6 grams daily for 8 weeks reduces anxiety and depression when compared with placebo in menopausal adults aged 50-60 years. The treatment has no effect on vasomotor symptoms or hormone levels (18310).
Mental alertness. It is unclear if oral blue-green algae are beneficial for reducing mental fatigue. Details: A preliminary clinical study shows that taking spirulina blue-green algae (Hawaiian Spirulina, Cyanotech Corporation) 3 grams daily for up to 8 weeks improves performance on a mathematical based mental fatigue test in healthy men when compared with placebo. Subjective improvement in mental alertness over placebo was also reported (97203).
Metabolic syndrome. It is unclear if oral blue-green algae are beneficial in patients with metabolic syndrome. Details: A small clinical study in patients with metabolic syndrome shows that taking spirulina blue-green algae (Spirulysat, AlgoSource), providing phycocyanin 20 mg, daily for 12 weeks improves triglyceride levels, but does not reduce body mass index, waist circumference, blood pressure, glycemic indices, or other lipid levels, when compared with placebo (109971).
Nonalcoholic fatty liver disease (NAFLD). Although there has been interest in using oral blue-green algae for NAFLD, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
Obesity. Evidence for the use of blue-green algae in obesity is conflicting. Details: Small, low-quality clinical trials have shown mixed results in people with obesity (18295,91717,97205,99655,99703,102688). When results are analyzed together, there is evidence of a very small benefit for both body weight and plasma lipid levels. Two meta-analyses show that taking spirulina blue-green algae may increase weight loss by up to 1.85 kg when compared with placebo (102690,104565). A greater effect is seen in patients with obesity when compared with overweight patients. In addition, there is a small effect on fat loss (102690). However, there is evidence from two studies lasting longer than 12 weeks that taking blue-green algae may slightly increase BMI (104565). A meta-analysis of small clinical trials also shows that taking spirulina blue-green algae reduces fasting blood sugar and total cholesterol levels by a small amount when compared with placebo, but has no effect on low-density lipoprotein (LDL) cholesterol or triglyceride levels, in patients with obesity (102689). When combined with an exercise program, taking spirulina blue-green algae increases weight loss by 1.4 kg and improves exercise tolerance and total, LDL, and high-density lipoprotein (HDL) cholesterol levels when compared with exercise alone (99655,102688). Doses have included a specific product containing the spirulina blue-green algae species A. fusiformis (Multinal, New Ambadi Estate Pvt. Ltd.) 1 gram twice daily or four times daily for 3 months (91717) or spirulina blue-green algae 2 grams daily for 3 months, or 4.5 grams daily for 6 weeks, alone or in combination with exercise (97205,99655,102688).
Oral leukoplakia. It is unclear if oral blue-green algae are beneficial for oral leukoplakia in tobacco chewers. Details: Preliminary clinical research shows that taking spirulina blue-green algae (A. fusiformis) orally 1 gram daily for 12 months produces regression of precancerous oral leukoplakia lesions in 45% of tobacco chewers, compared to only 7% of those receiving placebo. Regression rates appear to be highest in those with homogeneous lesions and lowest in those with ulcerated or nodular lesions (15782).
Periodontitis. It is unclear if injecting blue-green algae into periodontal pockets is beneficial in periodontitis. Details: Preliminary clinical research shows that injecting a 4% w/v gel prepared from spirulina blue-green algae into periodontal pockets of adults with chronic periodontitis, after scaling and root planing, is associated with a decrease in probing pocket depth of 1.57 mm after 120 days, compared with only 0.84 mm in patients receiving scaling and root planing alone (91709).
Premenstrual syndrome (PMS). Although there has been interest in using oral blue-green algae for PMS, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
Stress. Although there has been interest in using oral blue-green algae for stress, there is insufficient reliable information about the clinical effects of blue-green algae for this condition.
Ulcerative colitis. It is unclear if oral blue-green algae are beneficial in patients with ulcerative colitis. Details: A small clinical study in patients with ulcerative colitis shows that taking spirulina blue-green algae 500 mg twice daily for 8 weeks improves quality of life scores and reduces stress and sleep disturbances when compared with placebo. However, there was no effect on most measures of sleep quality, mood, and fatigue (109969).
Wound healing. Although there has been interest in using oral blue-green algae for wound healing, there is insufficient reliable information about the clinical effects of blue-green algae for this condition. More evidence is needed to rate blue-green algae for these uses.

Colorectal cancer. Consumption of cruciferous vegetables, including broccoli, seems to reduce the risk of developing colorectal cancer. Details: Epidemiological research has found that the highest intakes of cruciferous vegetables, including broccoli, are associated with an 18% to 20% reduced risk of developing colorectal neoplasms when compared with the lowest intakes (14148,96187,96189).

Bladder cancer. It is unclear if consumption of broccoli reduces the risk of developing bladder cancer. Details: Epidemiologic research has found that eating about 1.75 cups daily of cruciferous vegetables, such as broccoli or cabbage, is associated with a 30% reduced risk of developing bladder cancer (14864).
Breast cancer. It is unclear if consumption of broccoli reduces the risk of developing breast cancer. Details: Epidemiological research has found that consumption of broccoli is associated with a modestly reduced risk of developing breast cancer in premenopausal adults. However, broccoli consumption does not seem to be associated with breast cancer risk in postmenopausal adults (14146).
Fibromyalgia. Broccoli has only been evaluated in combination with ascorbigen; its effect when used alone is unclear. Details: A small clinical study in females with fibromyalgia shows that taking one capsule containing ascorbigen 100 mg and broccoli powder 400 mg once daily for one month improves pain by 18% and reduces physical impairment by 20% when compared with baseline (19605). It is unclear if this effect is due to broccoli, ascorbigen, or the combination. The validity of these findings is limited by the lack of a comparator group.
Gastric cancer. It is unclear if consumption of broccoli reduces the risk of developing gastric cancer. Details: A small epidemiological study has found that higher consumption of broccoli is associated with a reduced risk of developing gastric cancer when compared with lower consumption (14148).
Hypercholesterolemia. Broccoli has only been evaluated in combination with cabbage; its effect when used alone is unclear. Details: A small clinical study in patients with mild to moderate hypercholesterolemia shows that consuming 160 grams of a beverage containing broccoli, cabbage, and fruit twice daily for 12 weeks reduces levels of low-density lipoprotein (LDL) cholesterol by 8.5% when compared with baseline. It is unclear if the improvement from baseline differed when compared with those consuming a similar beverage without broccoli and cabbage (19607). It is unclear if this effect is due to broccoli, cabbage, or the combination.
Prostate cancer. It is unclear if consumption of broccoli reduces the risk of developing prostate cancer; the available research is conflicting. In patients with prostate cancer, broccoli has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some epidemiological research has found that consumption of Brassica vegetables, such as broccoli, Brussels sprouts, cauliflower, and cabbage, is associated with a reduced risk of developing prostate cancer (14145). However, other epidemiological research has found no association (14147,15172). Clinical research in adults with prostate cancer shows that taking a whole food formulation containing broccoli powder 100 mg, turmeric powder 100 mg, pomegranate whole fruit powder 100 mg, and green tea extract 20 mg three times daily for 6 months prevents an increase in prostate specific antigen (PSA) levels. Mean PSA levels increased by 15% in the whole food formulation group, compared with 79% in the placebo group. Also, 46% of those taking the whole food formulation showed final PSA levels that were the same or lower than initial PSA levels, compared with 14% of those in the placebo group (89730). However, it is not yet known whether the whole food formulation reduces the risk of prostate cancer progression or recurrence. It is unclear if these effects are due to broccoli, other ingredients, or the combination. More evidence is needed to rate broccoli for these uses.

BRUSSELS SPROUT (organic Brussels Sprouts powder)

Benign prostatic hyperplasia (BPH). Population research has found that higher intake of Brussels sprout is not associated with significantly reduced risk of BPH (26190).
Bladder cancer. Epidemiologic research has found that eating about 1 cup daily of cruciferous vegetables, such as cabbage, Brussels sprout, cauliflower, broccoli, kale, or collards, is associated with a 30% lower risk of developing bladder cancer in adults (14864). Other population research has found that higher intake of cruciferous vegetables, such as cauliflower, Brussels sprout, cabbage, broccoli, and kale, is associated with a 51% reduction in the risk of developing bladder cancer in males. However, higher intake of Brussels sprout alone does not seem to be associated with a reduced risk of bladder cancer (26184).
Breast cancer. Some population research has found that higher intake of cruciferous vegetables, including broccoli, Brussels sprout, cabbage, cauliflower, collards, and kale, is associated with a slight increase in the risk of breast cancer in premenopausal adults, while higher intake appears to be associated with a slight but statistically insignificant decrease in the risk in postmenopausal adults (26188). However, other population research has found that higher intake of Brussels sprout alone is not associated with a reduced risk of breast cancer (26189). Cruciferous vegetables might increase urinary levels of 2-hydroxyestrone, and its ratio to 16-alpha-hydroxyestrone, which could reduce the risk of breast cancer. However, research in pre-menopausal adults shows that taking a dried Brussels sprout and kale supplement, 3.3 grams daily for 8 weeks, or increasing dietary intake of Brussels sprout or broccoli by one 40-gram serving daily, does not increase urinary levels of 2-hydroxyestrone, or its ratio to 16-alpha-hydroxyestrone, when compared with placebo (112086).
Diabetes. Population research has found that higher intake of cruciferous vegetables, including broccoli, cabbage, cauliflower, and Brussels sprout, is not associated with a reduced risk of developing type 2 diabetes (26187). A meta-analysis of 23 studies shows that the highest levels of combined vegetable and fruit intake are associated with a 7% reduction in the risk of developing type 2 diabetes, when compared with the lowest intakes, but higher intake of Brussels sprout alone is associated with a 7% increase in the risk (112088).
Hypertension. A meta-analysis of 18 studies in healthy adults shows that the highest levels of combined vegetable and fruit intake are associated with a 9% to 11% reduction in the risk of developing hypertension, when compared with the lowest intakes, but higher intake of Brussels sprout alone is associated with a 25% increase in the risk (112087).
Lung cancer. Population research has found that people who consume Brussels sprout and broccoli at least once weekly have a 22% lower risk of developing lung cancer when compared with those who consume these vegetables less than once monthly (26192).
Non-Hodgkin lymphoma. Population research has found that females who consume at least half a serving of Brussels sprout or other cruciferous vegetables daily have a lower risk of developing non-Hodgkin lymphoma, particularly the follicular lymphoma subtype, when compared to those who eat these vegetables less often. However, eating Brussels sprout and other cruciferous vegetables does not appear to be associated with a reduced risk of non-Hodgkin lymphoma in males (26186).
Pancreatic cancer. Population research has found that consuming higher amounts of Brussels sprout is not associated with a reduced risk of pancreatic cancer (26181).
Prostate cancer. Population research has found that people who consume higher amounts of Brussels sprout and other cruciferous vegetables have a lower risk of developing prostate cancer (25420,25421).
Stroke. Population research has found that higher intake of Brussels sprout and other cruciferous vegetables is associated with a 32% reduction in the risk of ischemic stroke (7394). More evidence is needed to rate Brussels sprout for these uses.

Breast engorgement. Most research shows that applying cabbage leaves to engorged breasts reduces pain and hardness to the same degree as cold compresses in lactating females with breast engorgement. Details: Several small clinical studies suggest that applying whole cabbage leaves to the engorged breasts of lactating females produces subjective relief similar to the use of chilled gel-packs (6781,6784,93677). Both chilled and room temperature cabbage leaves seem to provide the same relief (6782). Another small clinical study shows that whole cabbage leaves also seem to improve breast pain and hardness when compared with general nursing care (93673). When compared with hot and cold compresses, one small clinical study found that using chilled cabbage leaves reduces postnatal breast engorgement to a similar degree, but is not as effective for reducing pain (101966). The preparation of cabbage leaves for this purpose sometimes includes stripping out the large vein of the cabbage leaf and cutting a hole for the nipple. Cabbage leaves are rinsed and chilled. The chilled cabbage leaf is worn inside the bra or as a compress under a cool towel. This procedure is typically repeated 1-4 times daily for 1-3 days (6781,6784,93673,93677,101966). A cabbage leaf extract applied as a cream has also been tried. The cabbage leaf extract cream seems to provide subjective relief when compared to baseline, but it does not provide superior relief when compared with a placebo cream (6783).

Bladder cancer. It is unclear if consuming cabbage is effective for the prevention of bladder cancer. Details: Observational research has found that eating about 1.75 cups of cruciferous vegetables such as cabbage or broccoli is associated with a 30% reduced risk of bladder cancer in men and women (14864).
Colorectal cancer. It is unclear if consuming cabbage is effective for the prevention of colorectal cancer. Details: Observational research has found that consuming large amounts of cabbage and other Brassica vegetables such as kale, broccoli, and cauliflower is associated with a lower risk of developing colorectal cancer (6792).
Gastric cancer. It is unclear if consuming cabbage is effective for the prevention of gastric cancer. Details: Observational research has found that consuming large amounts of cabbage and other Brassica vegetables such as kale, broccoli, and cauliflower is associated with a lower risk of developing stomach cancer (6792).
Gastritis. Although there has been interest in using oral cabbage for gastritis, there is insufficient reliable information about the clinical effects of cabbage for this purpose.
Hyperlipidemia. It is unclear if oral cabbage is beneficial in patients with hyperlipidemia. Details: A small clinical study in Japanese adults with hyperlipidemia shows that adding broccoli and cabbage to a beverage consisting of fruits and vegetables for 3-9 weeks reduces low-density lipoprotein (LDL) cholesterol levels by 8.5% when compared to baseline. The reduction in LDL cholesterol was significant when compared with the same beverage without broccoli and cabbage added (25423).
Knee pain. It is unclear if topical cabbage is beneficial in patients with knee pain. Details: A small clinical study in males with an acute mild to moderate traumatic knee ligament injury shows that use of crushed fresh cabbage leaf and cooling dressing wraps improves recovery over the first 24 hours of use by a moderate amount when compared with the cooling dressing alone. Normal fluid release occurred in 67% to 80% of patients using crushed cabbage leaf compared with 47% to 50% of those given the cooling dressing alone (101969).
Lung cancer. It is unclear if consuming cabbage is effective for the prevention of lung cancer. Details: Observational research has found that consuming large amounts of cabbage and other Brassica vegetables such as kale, broccoli, and cauliflower is associated with a lower risk of developing lung cancer (6792).
Osteoarthritis. Small clinical studies suggest that topical cabbage leaf modestly improves pain and other symptoms in patients with osteoarthritis of the knee. Details: A small clinical study in patients with osteoarthritis of the knee shows that applying cabbage leaf wraps to the knees for at least 2 hours daily for 4 weeks decreases pain by around 12 points on a 100 mm visual analog scale when compared with usual care. The analgesic effect of cabbage leaf wraps in these patients appears to be similar to treatment with topical gel containing the nonsteroidal anti-inflammatory drug diclofenac 10 mg/gram (93671). Another small, open-label clinical study in patients with moderate to severe osteoarthritis of the knee shows that applying cabbage leaf wraps to the knees for 1 hour daily for 4 weeks reduces knee pain and improves symptom severity when compared with diclofenac gel applied four times daily. Improvements in pain and overall symptoms were similar between cabbage leaf and the use of cooling gel pads (110558). The validity of these findings is limited by a lack of blinding.
Pancreatic cancer. It is unclear if consuming cabbage is effective for the prevention of pancreatic cancer. Details: Observational research in elderly and middle-aged individuals has found that consuming one or more servings of cabbage per week is associated with a 38% lower risk of developing pancreatic cancer when compared with those who do not eat cabbage (25422).
Peptic ulcers. Although there has been interest in using oral cabbage for peptic ulcers, there is insufficient reliable information about the clinical effects of cabbage for this purpose.
Prostate cancer. It is unclear if consuming cabbage is effective for the prevention of prostate cancer. Details: Some observational research has found that consuming higher amounts of cabbage and other Brassica vegetables such as kale, broccoli, and cauliflower is not associated with a lower risk of prostate cancer (25417,25419). However, other observational studies have found that consuming higher amounts of cabbage and other Brassica vegetables is associated with a lower risk of developing prostate cancer (25418,25420,25421). More evidence is needed to rate cabbage for these uses.

Vitamin A deficiency. Some preliminary clinical research shows that consuming one spoonful of carrot jam daily for 10 weeks improves growth velocity when compared with control in children with vitamin A deficiency (25819). Other preliminary research shows that consuming 100 grams of grated carrot daily for 60 days improves vitamin A status when compared with placebo in lactating women at risk for vitamin A deficiency (67861).

Breast cancer. A meta-analysis of observational research has found that consuming a diet highest in carrots is associated with a 21% decreased odds of developing breast cancer when compared with consuming a diet lowest in carrots (101715).
Colorectal cancer. A large observational study in older Danish adults shows that self-reported high consumption of raw carrot (2-4 carrots weekly or greater than 32 grams daily) is associated with a 17% lower likelihood of colorectal cancer diagnosis, whereas lower carrot consumption is not associated with a decreased risk. The validity of these findings may be limited by selection bias, recall bias, and other confounding factors (106559).
Fibromyalgia. Preliminary clinical research shows that consuming a mostly raw, pure vegetarian diet that includes two to four 240 mL servings of carrot juice daily for 7 months might improve fibromyalgia symptoms in some people (98057). The effect of carrot alone on fibromyalgia is unknown.
Prostate cancer. Population research has found that higher intake of carrot is associated with an 18% decrease in the odds of developing prostate cancer. Increasing carrot consumption by 10 grams daily or 1 serving per week is associated with a 4% to 5% decrease in the odds of developing prostate cancer (96307). More evidence is needed to rate carrot for these uses.

Anxiety. It is unclear if oral celery seed extract is beneficial in patients with anxiety. Details: A small clinical study in Iranian adults with hypertension on standard antihypertensive therapy shows that taking celery seed extract 1.34 grams daily for 4 weeks reduces symptoms of anxiety and depression when compared with placebo (112409). However, it is unclear if these benefits can be extrapolated to patients in geographic locations other than Iran.
Depression. It is unclear if oral celery seed extract is beneficial in patients with depression. Details: A small clinical study in Iranian adults with hypertension on standard antihypertensive therapy shows that taking celery seed extract 1.34 grams daily for 4 weeks reduces symptoms of anxiety and depression when compared with placebo (112409). However, it is unclear if these benefits can be extrapolated to patients in geographic locations other than Iran.
Diabetes. It is unclear if oral celery seed extract is beneficial in patients with diabetes. Details: A small clinical study in adults with type 2 diabetes shows that taking celery seed powder 250 mg three times daily for 12 weeks does not improve fasting blood glucose, fasting insulin, insulin resistance, total cholesterol, low-density lipoprotein or high-density lipoprotein cholesterol, triglycerides, or blood pressure when compared with placebo (112411). However, the study may have been inadequately powered to detect a difference between groups.
Dysmenorrhea. Oral celery seed has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical trial in female college students shows that taking a specific combination product containing celery seed, saffron, and anise extracts (SCA, Gol Daro Herbal Medicine Laboratory) 500 mg three times daily for 3 days, starting at the beginning of bleeding or pain, reduces severity and duration of pain symptoms associated with menstruation when compared with placebo (17214). It is not clear if these effects are due to celery, other ingredients, or the combination.
Dyspepsia. Oral celery seed has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical trial in adults with functional dyspepsia conducted in Iran shows that taking celery seed powder 500 mg daily with bishop's weed 500 mg daily spread over three doses after meals for 4 weeks reduces patient-reported dyspepsia symptom severity when compared with domperidone. Taking celery and bishop's weed also reduces patient-reported symptom frequency when compared to baseline (112410). However, it is unclear if these effects are due to celery, bishop's weed, or the combination, or if results can be extrapolated to patients in geographic locations other than Iran. The interpretation of these results is also limited by the lack of a placebo group.
Gout. Oral celery 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 gout shows that taking a specific combination product (GoutFigher, Max Biocare) containing celery seed extract 600 mg, devil's claw root extract 300 mg, sour cherry extract 200 mg, and other ingredients twice daily for 45 days reduces pain, joint inflammation, and uric acid levels when compared to baseline (106488). The validity of these findings is limited by the lack of a control group. Additionally, it is unclear if these findings are due to celery, other ingredients, or the combination.
Headache. Although there has been interest in using oral celery for headache, there is insufficient reliable information about the clinical effects of celery for this purpose.
Hypertension. It is unclear if oral celery seed extract is beneficial in patients with hypertension. Details: A small clinical study in Iranian adults with hypertension on standard antihypertensive therapy shows that taking celery seed extract 1.34 grams daily for 4 weeks reduces daytime systolic blood pressure by about 12 mmHg compared to less than 1 mmHg with placebo. Celery seed extract also reduces night-time blood pressure, diastolic blood pressure, and mean arterial pressure, but does not impact the heart rate (110755). However, it is unclear if these benefits can be extrapolated to patients in geographic locations other than Iran.
Impaired glucose tolerance (prediabetes). It is unclear if oral celery leaf extract is beneficial in patients with prediabetes. Details: A small clinical study in elderly patients with prediabetes shows that taking celery leaf extract 250 mg three times daily for 12 days reduces postprandial plasma glucose levels, but not insulin levels, when compared to baseline (99572). Although a control group was included in the study, statistical comparisons between treatment and control groups were not reported.
Mosquito repellent. It is unclear if topical celery seed extract is beneficial for use as a mosquito repellant. Details: One small clinical study shows that applying gel formulations containing celery seed extract 5% to 25% can repel mosquitos in a dose-dependent manner for up to 4.5 hours. These formulations show similar repellant action when compared with DEET-containing formulations and appear to be superior to commercial repellants without DEET (40988). Celery extract has also been evaluated in combination with other ingredients. Two clinical studies show that application of a specific formulation (G10, E.A.R. Samunpri) containing celery seed extract 5%, along with vanillin, eucalyptus oil, orange oil, and citronella oil, seems to repel mosquitos for up to 4.5 hours comparably to other commercial products, including DEET 25% and Insect Block 28 (41049,41052). It is unclear if these findings are due to celery, other ingredients, or the combination.
Osteoarthritis. Oral celery seed has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small, open-label clinical study in patients with mild knee osteoarthritis shows that taking a specific combination product (Tregocel, Max Biocare) providing celery seed 1000 mg, Boswellia serrata resin extract 1000 mg, devil's claw 1000 mg, ginger rhizome 330 mg, and curcumin 180 mg daily for 36 weeks reduces pain, improves functional capacity, and increases walking distance when compared to baseline (106078). The validity of these findings is limited by the lack of a control group. Additionally, it is unclear if these findings are due to celery, other ingredients, or the combination.
Rheumatoid arthritis (RA). Although there has been interest in using oral celery juice for RA, there is insufficient reliable information about the clinical effects of celery for this purpose.
Sexual dysfunction. It is unclear if oral celery seed powder is beneficial in females with sexual dysfunction. Details: One small clinical study in females with sexual dysfunction shows that taking celery seed powder 500 mg three times daily for 6 weeks improves sexual dysfunction symptom scores, primarily due to patient-rated improvements in sexual desire, arousal, lubrication, and pain, when compared with placebo (106486).
Urinary tract infections (UTIs). Although there has been interest in using oral celery juice for UTIs, there is insufficient reliable information about the clinical effects of celery for this purpose. More evidence is needed to rate celery for these uses.

Bladder cancer. Observational research has found that eating about 0.88 cups of cruciferous vegetables, such as cabbage, Brussels sprout, cauliflower, broccoli, kale, or collards, decreases the risk of developing bladder cancer by about 30% in men and women (14864).
Breast cancer. Population research has found that higher intake of cruciferous vegetables, including broccoli, Brussels sprout, cabbage, cauliflower, collards, and kale, is associated with a slight increase in the risk of breast cancer in premenopausal women, while higher intake of cruciferous vegetables appears to be associated with a slight but statistically insignificant decrease in the risk of breast cancer in postmenopausal women (26188).
Prostate cancer. Population research has found that people who consume higher amounts of green leafy vegetables, such as collard, spinach, mustard greens, and turnip greens, do not have a significantly lower risk of developing prostate cancer when compared with those who eat lower amounts (25420). More evidence is needed to rate Brussels sprout for these uses.

FOLIC ACID

EFFECTIVE

Folate deficiency. Oral or intravenous folic acid is effective for the prevention or treatment of folate deficiency. Details: Administering folic acid orally or parenterally improves and prevents folate deficiency (505,8739). Clinical research shows that supplementation with folic acid 100 mcg to 5 mg daily during pregnancy decreases the risk of developing megaloblastic anemia by up to 79% (91307).

Kidney failure. Taking folic acid orally reduces homocysteine levels in people with kidney failure who are on hemodialysis. Details: Over 85% of people with kidney failure have hyperhomocysteinemia. Treatment of hyperhomocysteinemia in kidney failure is often more difficult than with normal kidney function (1489,3324,7289,9413,9414,9416). The reasons for this are not fully understood; renal uptake and metabolism of homocysteine may be reduced in severe kidney failure, and hemodialysis may contribute to vitamin deficiencies (6884,9414,9417). Folic acid 0.8-15 mg daily or 3 times weekly is generally used, but the degree of homocysteine reduction varies between 12% to 50%, and normal homocysteine levels (less than 12 µmol/L) cannot always be achieved. Adding vitamin B12 400-1000 mcg daily and vitamin B6 20-50 mg daily produces an additional reduction in homocysteine (1489,6884,7289,7881,9322,9413,9414,9415,9416,9417). Folic acid doses greater than 15 mg daily do not seem to provide additional benefit. Also, doses of 30-60 mg might cause a rebound in homocysteine levels when treatment is stopped (9219). Despite the homocysteine-lowering effect of folic acid in kidney failure, the most robust meta-analysis of 11 clinical trials suggests that folic acid supplementation does not seem to reduce the risk of cardiovascular events (50527). A smaller meta-analysis of 7 clinical trials that used a different primary composite outcome suggests that folic acid might reduce the risk of cardiovascular events by 15% when compared with control (91311). There has also been interest in using a reduced form of folic acid, L-5-methyltetrahydrofolate (L-5-MTHF). One study in patients on hemodialysis suggests that taking L-5-MTHF 17 mg daily for 12 weeks might lower homocysteine levels to a greater extent than an equimolar 15 mg of folic acid (104908). Another clinical trial in patients on hemodialysis suggests that giving intravenous L-5-MTHF 50 mg three times weekly is associated with an increased survival of about 36 months, compared with about 26 months with folic acid 5 mg daily. There was no difference in homocysteine reduction between groups (104909). These results should be interpreted with caution because they have not been replicated, and there was no placebo control. Furthermore, survival may have been affected by the availability of kidney transplants.
Hyperhomocysteinemia. Oral folic acid, taken alone or in combination with other B vitamins, lowers homocysteine levels in most patients. However, it is unclear if this has cardiovascular benefits. Details: Taking folic acid orally 0.4-5 mg daily lowers fasting homocysteine levels by 20% to 30% in people with normal to moderately elevated homocysteine levels at baseline. Folic acid 0.8-1 mg daily seems to provide maximal reduction (9307,9400,9401,9405,9408,11337,11338,50145). Doses above 1 mg daily do not seem to add benefit (9307), except in some people with certain gene mutations that cause homocysteine levels of 20 µmol/L or higher (9408). The higher the initial homocysteine levels, the lower the folic acid dose needed to attain maximum homocysteine reduction (9307). The effects of folic acid supplementation on homocysteine concentrations appear to be greater in females than males (50145). Adding vitamin B6 25-250 mg or vitamin B12 500 mcg seems to further reduce homocysteine levels (1489,9400,9405,9406,9408,107136). Some experts recommend routine use of vitamin B12 in homocysteine-lowering regimens to avoid the risk of neuropathy in people with undetected vitamin B12 deficiency (9405). Increasing folic acid intake with supplements or folate-fortified cereal products is more effective for reducing homocysteine levels than increasing intake of folate-rich foods (6367). Fortification of cereals and flour with 140 mcg folic acid per 100 grams reduces the mean homocysteine level in the general population by about 7% (7881,9404,9407). Elevated homocysteine levels are considered by some to be an independent risk factor for atherosclerosis progression, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, ischemic stroke, and other vascular complications (3886,3887,6236,7725,9314,9318,50509). However, elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). Although folic acid lowers homocysteine levels, it is not yet known whether this reduces the risk of vascular disease. One meta-analysis shows that taking folic acid can reduce the risk of stroke by about 10% in patients with cardiovascular disease (CVD); the reduction is greatest in patients for whom homocysteine levels are lowered by at least 25% (96157). A meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo (97619). Also, a meta-analysis in patients with a history of stroke shows that B vitamin supplementation, including folic acid, reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136). However other research does not agree. Meta-analyses of clinical research show that folic acid does not prevent CVD or coronary heart disease, in spite of lowering homocysteine by up to 55%, when individuals with normal or high levels of homocysteine are considered (50539,96147,97619). Furthermore, most research shows that folic acid supplementation, alone or in combination with vitamin B6 and vitamin B12, does not improve endothelial function or improve secondary prevention of cardiovascular events such as myocardial infarction in people with existing CVD despite a homocysteine-lowering effect (9313,11337,11387,13482,50437,97619). Some research even suggests an increase in CVD risk concurrent with homocysteine lowering (13482). Large randomized controlled trials are needed to confirm or refute these findings. Some researchers hypothesize that different genetic profiles might explain some of these conflicting results. For instance, individuals with a homozygous 677TT MTHFR genotype typically have increased homocysteine levels. However, a meta-analysis suggests that treatment with folic acid does not reduce the risk of ischemic heart disease despite reducing homocysteine levels in individuals with 677TT MTHFR (50456). It has also been theorized that a reduced form of folic acid, 5-methyltetrahydrofolate (5-MTHF) might work better in these individuals. Although [6RS]-5-MTHF has been shown to lower homocysteine levels (104915), studies assessing its cardiovascular benefits are lacking.
Methotrexate toxicity. Oral folic acid reduces the severity of methotrexate toxicity. Details: Oral folic acid reduces methotrexate toxicity symptoms, such as nausea and vomiting, in the treatment of rheumatoid arthritis (RA) and psoriasis (768,2162,2163,2164,4492,4493,4494,9369,9419). Folic acid also seems to reduce methotrexate-induced hepatic side effects by approximately 36% (50320). Some research shows that a low, 0.8 mg weekly dose of folic acid is equally effective to a higher dose of 5 mg weekly for the prevention of methotrexate toxicity (102388).
Neural tube birth defects. Oral folic acid helps to prevent neural tube birth defects in newborns. Details: Clinical practice guidelines recommend that anyone capable of becoming pregnant take folic acid 400 mcg daily from fortified foods or supplements to prevent neural tube birth defects in infants. Folic acid 600 mcg daily is advised during pregnancy (94811,96146). This recommendation is based on research showing that a higher intake of folic acid from food and supplements during pregnancy reduces the primary incidence of neural tube birth defects by 41% to 69% (3325,9309,50344,50403,50468,95156). Individuals with a history of children with neural tube birth defects usually take a higher dose of folic acid 4000 mcg daily starting one month before and continuing for up to 3 months after conception (96146). Evidence shows that, when used for secondary prevention, folic acid supplementation reduces the incidence of neural tube defects by 66% to 87% (21235,50263,50344,50403,95156). In the US, foods containing at least 60 mcg of folic acid can be labeled with a health claim stating that healthful diets with adequate folic acid intake may reduce the risk of having a child with a brain or spinal cord defect (102369).

Cognitive impairment. Taking folic acid alone, with other B vitamins or with docosahexaenoic acid (DHA), might improve thinking and memory skills in older patients with cognitive impairment. Details: One clinical trial in patients aged 65 years and older with mild cognitive impairment (MCI) shows that taking folic acid 400 mcg daily for 2 years increases IQ scores when compared with placebo (100952). Two small, low-quality clinical studies in patients aged 70-90 years with cognitive impairment and low folate levels or folate deficiency shows that taking folic acid 5 or 15 mg daily for up to 63 days improves cognitive function, including measures such as memory and attention, when compared with placebo or baseline (50301,104911). Folic acid also appears to be beneficial when used in combination with other B vitamins or with DHA. A clinical trial in patients aged 70 years and older with MCI shows that taking folic acid 800 mcg, vitamin B6 20 mg, and vitamin B12 500 mcg daily for 2 years mitigates decline in executive function and, in patients with high baseline homocysteine levels, improves cognition and memory when compared with placebo (50480). Taking folic acid 800 mcg with or without DHA 800 mg daily for 6 months modestly improves cognition, as measured on the full-scale intelligence quotient, when compared with placebo (103978,109196). However, this benefit is no longer present at 6 months after treatment discontinuation (109196).
Depression. Oral folic acid seems to modestly reduce depression severity when added to conventional antidepressant therapy. It is unclear if folic acid can reduce the prevalence of depression or the risk for suicide. Details: Observational studies suggest that depression is correlated with low folate status, particularly in females (50105,50127,50243). Taking folic acid 0.2-15 mg daily for up to 6 months with conventional antidepressants seems to improve treatment response in patients with major depressive disorder (3657,10884,10887,50566,109190). One meta-analysis shows that taking L-methylfolate or folic acid as an adjunct to treatment with conventional antidepressants modestly reduces depression severity when compared with placebo and conventional antidepressants. The response and remission rates were improved by 36% and 39%, respectively (109190). However, limited clinical research suggests that folic acid is not effective as a replacement for conventional antidepressant therapy (10886). Also, a small clinical study in adolescents at high familial risk for mood disorders suggests that taking folic acid 2.5 mg daily for up to 36 months does not prevent mood disorders when compared with placebo. However, in the patients that were eventually diagnosed with depression, the time of onset was delayed from 5 months to 15.5 months in the group using folic acid when compared with placebo (91313). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that folic acid is not currently recommended as monotherapy treatment for unipolar depression (110318). Observational research has also evaluated the association between folic acid supplementation and suicidal events in patients with or without depression. One within-person cohort study, in which only 12% of patients were diagnosed with depression, has found that filling a folic acid prescription of 0.4-5 mg daily, either alone or as part of a multivitamin, is associated with a reduced risk for suicidal events during the following months when compared with months without a prescription (109201). It is unclear what percentage of these patients, if any, had folate deficiency at baseline.
Hypertension. Oral folic acid seems to modestly reduce hypertension. Details: A meta-analysis of clinical research shows that taking folic acid 5-10 mg daily for at least 6 weeks reduces systolic blood pressure by 2mmHg and improves flow-mediated dilation by 1.6% in hypertensive individuals (50364). Some research has evaluated folic acid in hypertensive patients when used with antihypertensive drugs. Results show that taking folic acid 400-800 mcg in combination with enalapril 10 mg daily for about 4.5 years does not improve blood pressure when compared with enalapril alone (50302,96158). However, in hypertensive patients with heavy proteinuria, this combination seems to reduce the risk of all-cause mortality by about 41% when compared with enalapril alone (96158).
Phenytoin-induced gingival hyperplasia. Topical folic acid seems to reduce gingival hyperplasia due to phenytoin. The effect of oral folic acid is unclear. Details: Applying folic acid topically seems to inhibit gingival hyperplasia secondary to phenytoin therapy (2151). However, taking folic acid orally does not seem to improve gingival hyperplasia secondary to phenytoin therapy in adults (2150,2151,2152), although some evidence suggests that taking folic acid 500 mcg daily reduces the risk of phenytoin-induced gingival hyperplasia by 33% in children when compared with placebo (50463).
Stroke. Although some clinical research has shown that oral folate reduces stroke risk by a small amount, more research is needed to determine who is most likely to benefit. Most individual clinical trials show that folic acid seems to reduce stroke risk only in regions without food-fortification policies. Details: Multiple clinical studies have shown that folic acid supplementation reduces the risk of stroke by 10% to 25% in regions WITHOUT established policies mandating folic acid fortification of grain products (50240,50485,50525,50539,91325,96154,96157,96159,97308). The effect appears to be greatest when folic acid is taken in low doses (usually 0.8 mg daily or lower) (50525,96157,96159), in regions with a low prevalence of statin use (50525,96159), in patients with high cholesterol levels at baseline (96152), in patients who achieve homocysteine reduction of at least 20% (50407,96157), and in patients with the lowest folate levels at baseline (96154,96157). There is also some evidence that the effect of folic acid on stroke risk is greatest in patients with low baseline levels of vitamin B12 (96159). In 2001, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Most research shows that folic acid supplementation does not reduce the risk of stroke in regions WITH established policies mandating folic acid fortification (50240,50485,50525,50539,96157,96159,97308). However, there is some evidence that folic acid may reduce the risk of stroke in patients from regions with folic acid fortification who have recently had a stroke or transient ischemic attack and are not using antiplatelet drugs (90379). Meta-analyses of clinical research have been conducted. However, possible confounding due to the presence or absence of folic acid fortification is unclear. A meta-analysis of the available research in adults with existing CVD shows that folic acid supplementation at a daily dose of less than 2 mg reduces the risk for stroke by about 10% (102386). Also, a meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation, including folic acid, reduces the relative risk of stroke by 10% when compared with placebo (97619). In patients with a history of stroke, a meta-analysis shows that B vitamin supplementation reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136). It is unclear if folic acid reduces the stroke risk in patients with impaired kidney function. Some research shows that taking folic acid in combination with high doses of vitamin B12 (cyanocobalamin) does not reduce the risk of stroke in these patients (11387,96150). However, there is concern that the lack of benefit may have been due to the decline in kidney function from high doses of cyanocobalamin (96150). Additional research is needed to determine if folic acid supplementation is beneficial in patients with impaired kidney function when used with other forms of vitamin B12 such as methylcobalamin or hydroxycobalamin.
Vitiligo. Oral folic acid seems to improve vitiligo symptoms. Details: Taking folic acid orally seems to improve symptoms of vitiligo (2153,2154). This finding is supported by a meta-analysis of observational research which shows that patients with vitiligo have higher serum homocysteine levels when compared with patients without vitiligo (100951).

Anemia. Adding oral folic acid to oral iron therapy does not seem to improve hematologic parameters in patients with anemia. Details: In postpartum patients with anemia, clinical research shows that taking iron as ferrous fumarate 600 mg and folic acid 1 mg daily is no more effective than iron alone for improving hemoglobin status (91319). Also, clinical research in non-pregnant menstruating females shows that taking folic acid 0.4 mg daily or 2.8 mg once weekly for 16 weeks with iron 60 mg daily does not reduce anemia or improve iron status when compared with iron alone (109193). During pregnancy, clinical research shows that folic acid supplementation does not decrease the risk of pre-delivery anemia or low hemoglobin levels (91307).
Age-related cognitive decline. Oral folic acid does not seem to prevent cognitive decline in healthy elderly adults. Details: Most clinical research shows that taking folic acid, alone or in combination with other B vitamins, does not improve cognitive function, including memory, language, or executive function, in elderly adults with age-related cognitive decline (50318,50412,50510). In fact, a large-scale observational study in the US has found that people over 65 years of age who consume large amounts of folic acid (median of 742 mcg daily) have cognitive decline at a rate twice as fast as those consuming smaller amounts (median of 186 mcg daily) (13068). While most research on folic acid for age-related cognitive decline lacks positive findings, many of the studies are small, short-term (<1 year), underpowered to detect significant differences, and not specific to patients with high homocysteine levels. Population research has found that high homocysteine levels are associated with decreased cognition in older adults, suggesting that using folic acid to lower homocysteine levels might mitigate cognitive decline in these patients (50094). Two long-term clinical trials examining the effects of folic acid in elderly adults with high homocysteine levels show mixed results. A large-scale clinical trial of patients aged 50-70 years from the Netherlands who have high homocysteine levels shows that taking folic acid 800 mcg daily for 3 years increases memory, information processing, and other measures of cognitive function when compared with placebo (15271). However, another large-scale clinical trial of patients aged 65 years and older from the Netherlands who have high homocysteine levels shows that taking folic acid 400 mcg and vitamin B12 500 mcg daily for 2 years lowers homocysteine levels, but does not appear to improve overall measures of cognitive function, when compared with placebo (90392). The reasons for the discrepant findings in these two studies are not clear but might relate to differences in the dose of folic acid, duration of treatment, and age of patients included.
Cataracts. Oral folic acid does not seem to reduce cataract development. Details: Clinical research in females with existing cardiovascular disease (CVD) or with risk factors for CVD shows that taking folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of developing cataracts. Furthermore, the risk of cataract extraction was increased by 28% in these patients (96149).
Diarrhea. Oral folic acid does not seem to reduce the risk of diarrhea, and might even increase the incidence of diarrhea in children. Details: In children aged 6-30 months at risk of malnourishment, clinical research shows that taking a nutritional supplement (Nutriset Ltd) enriched in folic acid 75-150 mcg, with or without vitamin B12 0.9-1.8 mcg, daily for 6 months does not reduce the incidence of diarrhea when compared with placebo. Enrichment with folic acid, with or without vitamin B12, actually seems to increase the likelihood of having more episodes of both persistent diarrhea and diarrhea lasting over 3 days (90391).
Fall prevention. Oral folic acid does not seem to reduce the risk of falls. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg daily, for 2 years, does not prevent falls when compared with placebo in elderly individuals also taking vitamin D (96148).
Fetal and premature infant mortality. Oral vitamin B12 does not seem prevent mortality in premature infants. Details: Clinical research shows that supplementation with folic acid during pregnancy does not decrease the risk of miscarriage, stillbirth, or neonatal death (91307,96156).
Leukemia. Oral vitamin B12 does not seem to reduce the risk for pediatric acute lymphoblastic leukemia. Details: A meta-analysis of results from two case-control studies has found that increased folate intake during pregnancy is not associated with a reduced risk of childhood acute lymphoblastic leukemia (50247).
Male infertility. Oral folic acid does not seem to improve sperm parameters or pregnancy rates in males with infertility. Details: Some small clinical studies show that taking folic acid, alone or with zinc, increases sperm count in males with idiopathic infertility or in males with a grade III varicocele (9334,90194). However, another small study in males with asthenozoospermia shows that taking folic acid 5 mg, selenium 200 mcg, and vitamin E 400 IU daily for 3 months does not improve sperm parameters when compared with placebo (104907). Furthermore, there seems to be no improvement in clinical outcomes. One large, high-quality clinical study in males with idiopathic infertility shows that taking folic acid 5 mg with zinc 30 mg daily for 6 months does not improve sperm morphology, pregnancy rate, or live birth rate when compared with placebo (102085). Folic acid has also been evaluated in combination with other ingredients. A retrospective study in males with or without varicocele-related infertility suggests that taking a specific combination product containing folic acid 0.2 mg, vitamin C, zinc, L-carnitine fumarate, acetyl-L-carnitine, coenzyme Q10, selenium, and vitamin B12 (Proxeed Plus, Sigma-Tau) twice daily for 6 months is associated with improvements in sperm count, sperm concentration, and sperm motility when compared to baseline. Improvement in semen parameters were greatest in subjects with more severe varicoceles (111296). The validity of this study is limited by the lack of a comparator group.
Osteoporosis. Oral folic acid does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in elderly adults or adults with a history of cerebrovascular disease shows that taking vitamin B12 500 mcg and folic acid 0.4-2 mg, with or without vitamin B6 25 mg, daily for 2-3 years does not seem to reduce the risk for osteoporotic fractures when compared with placebo (90377,90393). A 5-7 year follow-up of this research has also found no benefit (103981).
Physical performance. Oral folic acid does not seem to improve physical performance in older adults. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg daily for 2 years, does not improve hand strength or improve performance such as walking when compared with placebo in elderly individuals also taking vitamin D (96148).
Pre-eclampsia. Oral folic acid does not seem to prevent pre-eclampsia in pregnant patients. Details: While the effect of low-dose prenatal folic acid is unclear, high-dose folic acid does not seem to reduce the risk of pre-eclampsia. Some population research has found that low-dose folic acid is associated with a 22% reduced odds of pre-eclampsia, while other research has found no association (91308,99370,99372,110447). A large clinical trial evaluating high-dose folic acid in pregnancies at risk for pre-eclampsia shows that taking 4 mg daily, starting at 8-16 weeks of gestation and continuing until delivery, does not reduce the risk of pre-eclampsia when compared with placebo (103929). A secondary analysis of this study in twin pregnancies has also found no benefit with high-dose folic acid supplementation (103977).
Respiratory tract infections. Oral folic acid does not seem to prevent respiratory tract infections. Details: Clinical research in children aged 6-30 months at risk of malnourishment shows that taking a nutritional supplement (Nutriset Ltd) enriched in folic acid 75-150 mcg, with or without vitamin B12 0.9-1.8 mcg, daily for 6 months does not reduce the incidence of lower respiratory infections when compared with a supplement not enriched with folic acid and vitamin B12 (90391).

LIKELY INEFFECTIVE

Colorectal adenoma. Oral folic acid does not prevent colorectal adenomas. Details: Although some population research and one clinical study has found that high folate intake is associated with reduced colorectal adenoma risk (2142,2143,91303), most clinical research does not support this finding. Clinical research shows that taking a combination of B vitamins, including folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily for up to 9.2 years, does not reduce the risk of colorectal adenoma in females at high risk of cardiovascular disease when compared with placebo (90389). Other clinical research suggests that taking folic acid does not reduce the occurrence or recurrence of adenomas or incidence of advanced adenomas (34596,50241,50265,50369,50394,50449,50522). Furthermore, treatment with folic acid for more than 3 years seems to be associated with an increased risk of advanced adenomatous lesions (50378).
Fragile X syndrome. Oral folic acid does not improve symptoms in children with fragile X syndrome. Details: Clinical research shows that taking folic acid orally does not improve symptoms of fragile X syndrome (2155,2156,2157,2158,2159,2160,50575).
Preterm labor. Oral folic acid does not seem to reduce the risk of preterm birth. Details: Meta-analyses of clinical research show that supplementation with folic acid 200 mcg to 5 mg during pregnancy does not decrease the risk of preterm birth (91307,96155). An observational study in patients with and without epilepsy found that folic acid supplementation during pregnancy was associated with a lower odds of preterm birth in patients receiving antiseizure medications; however, no link between folic acid and preterm labor was reported in patients without epilepsy or in those with epilepsy not receiving antiseizure medications (110447).

Abdominal wall defects. It is unclear if oral folic acid helps to prevent abdominal wall defects in newborns. Details: Observational research in a population in northern China has found that taking folic acid supplements until the end of the first trimester modestly reduces the risk of abdominal wall defects and the risk of omphalocele, specifically, in the newborn when compared with not taking folic acid. However, this association was not found in a population in southern China (109191). These differing outcomes may be related to the lower dietary folate intakes in northern China.
Acne. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults and children with inflammatory acne shows that taking 1-4 tablets of a specific product (NicAzel, Elorac Inc.) containing folic acid, vitamin B6, nicotinamide, azelaic acid, zinc, and copper for 8 weeks reduces inflammatory lesions and improves appearance in 88% and 81% of patients, respectively, when compared with baseline (90800).
Age-related macular degeneration (AMD). Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily reduces the risk of developing AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or with risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to folic acid, other ingredients, or the combination.
Age-related testosterone deficiency. Folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in males with overweight or obesity, mild erectile dysfunction, and normal to low androgen levels shows that taking a combination product containing folic acid 400 mcg, alpha-lipoic acid, myo-inositol, and apple (Sinopol Forte) increases testosterone, luteinizing hormone, and measures of erectile dysfunction but not follicle-stimulating hormone or sperm parameters when compared to baseline (111674). The validity of these effects is limited by the small sample size and the lack of a comparator group, and it is unclear if these effects are due to folic acid, other ingredients, or the combination.
Alzheimer disease. It is unclear if oral folic acid reduces the risk of developing this condition. Details: Low levels of folate and high levels of homocysteine have been linked to a greater risk of Alzheimer disease (50094). Also, some observational studies have found that higher intake of folate from the diet and supplements in elderly adults is associated with a reduced risk of developing Alzheimer disease when compared with lower intake (13165,15270). One small clinical trial in patients with Alzheimer disease who are taking cholinesterase inhibitors shows that taking folic acid 1 mg daily for 6 months increases the likelihood of treatment response, classified as global improvement in behavioral and/or functional status with no decline in mental status scores, by 78% to 87% when compared with placebo (50246). Also, preliminary clinical research in patients with probable Alzheimer disease who are not consuming a folate-fortified diet shows that taking vitamin B12 50 mcg daily plus folic acid 1.2 mg daily for 6 months modestly improves some measures of cognitive performance and decreases levels of homocysteine when compared with placebo (107150). However, not all research agrees. Clinical research in patients with probable Alzheimer disease using routine medications shows that taking folic acid 5 mg, vitamin B12 1 mg, and vitamin B6 25 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo (50319). However, all patients in this study were also consuming a folate-fortified diet.
Angioplasty. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that folic acid 1 mg, vitamin B12 400 mcg, and pyridoxine 10 mg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, vitamin B6, and vitamin B12 followed by oral administration of folic acid 1.2 mg, vitamin B6 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151).
Atopic dermatitis (eczema). It is unclear if oral folic acid during pregnancy reduces the risk of eczema in the child. Details: Observational research has found that consuming both iron and folic acid supplements during pregnancy is associated with a four-fold reduced risk for developing atopic dermatitis in the child. However, use of either iron or folic acid supplementation alone is not associated with an effect on the child's risk for atopic dermatitis (102387).
Autism spectrum disorder. It is unclear if oral folic acid intake during pregnancy reduces the risk of autism spectrum disorder in the child. Details: A meta-analysis of population research has found that consumption of folic acid of at least 400 mcg daily from both diet and supplements during pregnancy is associated with a 45% reduced risk of autism in the child at 2-15 years of age. Also, supplementation with folic acid during the prenatal to early period of pregnancy is associated with an approximate 43% reduced risk of autism in the child. This association did not differ between countries with or without a folate fortification program (109198). An individual population study has also found that prenatal folic acid supplementation initiated the first day of the last menstrual period before conception is associated with a 39% reduced odds of autism in the child at age 3.3-10.2 years when compared to pregnancies without folic acid supplementation (91324).
Beta-thalassemia. There is limited evidence on the oral use of folic acid for beta-thalassemia minor. Details: Patients with beta-thalassemia minor may experience decreased muscle strength and increased bone or muscle pain. A small clinical study in children with this condition shows that taking folic acid 1 mg, with or without L-carnitine 50 mg/kg, daily for 3 months reduces bone pain by 64% to 84% and increases the number of stairs climbed by 2- to 5-fold when compared with baseline (90631). The validity of this finding is limited by the lack of a control group.
Bipolar disorder. It is unclear if adding oral folic acid to conventional bipolar therapy further improves symptoms. Details: Some clinical evidence suggests that folic acid does not improve the antidepressant effects of lithium in patients with bipolar disorder (50566). However, other clinical evidence suggests that taking folic acid in combination with valproate during the acute phase of mania improves the effects of valproate (50357).
Breast cancer. It is unclear if oral folic acid reduces breast cancer risk. Details: Some older population research suggests that increased intake or levels of folic acid alone does not affect the risk of breast cancer or breast cancer-related mortality (50218,50224). However, in a specific group of women who also consume high amounts of dietary methionine, cyanocobalamin (vitamin B12), or pyridoxine (vitamin B6), dietary intake of folate is associated with a reduced risk of breast cancer (9328,50224). Also, more recent population research has found that folic acid plus folate dietary intakes between 153-400 mcg are associated with a reduced risk of breast cancer. This risk is further reduced in those who drink relatively large amounts of alcohol (90794). Folate intakes greater than 400 mcg daily do not appear to be protective against breast cancer (90794).
Cancer. It is unclear if oral folic acid prevents cancer. Details: A large cohort study of children born to mothers with epilepsy on antiseizure medications suggests that prenatal folic acid exposure of 1 mg daily or more, at an average of 4.3 mg daily, is associated with a 2.7-fold greater risk of pediatric cancer when compared with children born to mothers with epilepsy but without prenatal exposure to high-dose folic acid. Additionally, this risk is not present in children of mothers without epilepsy taking high-dose folate (112103). It is unclear how maternal epilepsy, antiseizure medications, and folate interact to increase the risk of pediatric cancers. However, in the absence of clear guidelines, mothers with epilepsy should take no more than 4 mg of folic acid daily (112101,112102).
Cardiovascular disease (CVD). Although oral folic acid does not seem to prevent most CVD events, some research suggests that increased dietary folic acid might lower the risk of stroke and CVD-related mortality in patients at high risk for CVD. Details: In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Meta-analyses of available research show that folic acid might lower the risk of stroke in patients with CVD (97619,102386,107136). Some clinical research shows that taking folic acid reduces the risk of CVD by 15% in patients with kidney failure or chronic kidney disease (50444,91311). However, most research shows that folic acid supplementation, alone or in combination with vitamin B6 and vitamin B12, does not improve endothelial function or reduce the risk of death or CVD events in patients with existing hyperhomocysteinemia, coronary heart disease, CVD, kidney disease, or prior stroke, despite having a homocysteine-lowering effect (9313,9322,11337,11387,13482,50437) (50512,50527,96154,96147,97619,102386). Some population research has evaluated adults at high risk for CVD. This research has found that dietary folate intake of at least 382 mcg daily is associated with a modest reduction in CVD-related mortality and possibly all-cause mortality. Consuming folic acid as a component of fortified food in doses of more than 251 mcg daily is associated with a modest reduction in CVD-related mortality. Conversely, folic acid supplementation is associated with a higher risk of CVD and overall mortality, and there is a J-shaped association between folate intake, serum folate levels, and red blood cell folate levels, with both CVD-related and all-cause mortality (109199).
Cervical cancer. It is unclear if oral folic acid prevents cervical cancer. Details: Epidemiological evidence has found that increasing folate intake from dietary and supplement sources, along with thiamine, riboflavin, and vitamin B12, might decrease the risk of precancerous cervical lesions (11074).
Child development. It is unclear if oral folic acid supplementation during pregnancy improves child development. Details: Clinical research in Northern Ireland shows that taking folic acid 400 mcg daily starting in the 14th week of gestation and continuing until the end of pregnancy improves word reasoning in the child at 7 years of age when compared with placebo. When compared with a historical cohort from Britain, folic acid supplementation was associated with an increase in full scale IQ, verbal IQ, performance IQ, and general language at 7 years of age (102385). At age 11, benefits in word reasoning were no longer significant. However, there were modest benefits in some measures of processing speed when compared with placebo. Verbal comprehension was modestly improved in females, but not males (109192). Observational research in pregnant individuals and their children in Spain has found that taking less than 400 mcg of folic acid daily during pregnancy is associated with lower mental alertness scores in children at ages 7-9 years when compared with folic acid 400-999 mcg daily, while taking folic acid 1000 mcg or more daily during pregnancy was associated with improvements in some measures of working memory in the children. However, no relationship between folic acid dosing and most other measures of cognitive function was identified (110449).
Chronic fatigue syndrome (CFS). Although there is interest in using oral or injectable folic acid for CFS, there is insufficient reliable information about the clinical effects of folic acid for this condition.
Chronic kidney disease (CKD). While adding oral folic acid to enalapril might slow CKD progression, adding folic acid to high-dose vitamin B12 does not seem to be beneficial. Details: Clinical research in adults with hypertension and CKD shows that taking enalapril with folic acid 800 mcg for a median of 4.4 years reduces the risk of worsening kidney function by 21% and slows the rate of kidney function decline by 44% when compared with enalapril alone (96153). However, clinical research does not support the use of folic acid in patients with CKD when used in combination with high-dose vitamin B12 (cyanocobalamin). Vitamin B12 might increase the risk of negative outcomes (50253,50409,96150). More research is needed to determine the benefits of folic acid when used alone.
Colorectal cancer. It is unclear if oral folic acid prevents colorectal cancer. Details: Although the majority of population research suggests that taking folic acid orally from dietary and supplemental sources reduces the risk of colorectal cancer (505,2140,2144,2145,2250,6271,9325,9326,50109,50427,50450)(91306,91323,96160,109188,110450), clinical evidence in general is not supportive. Most clinical research and meta-analyses of clinical trials suggest that taking folic acid from dietary or supplemental sources does not reduce the risk of colorectal cancer (2141,34596,50394). The reason for this discrepancy is unclear. Some observational research suggests that an inverse association between folate intake and risk of colorectal cancer was not apparent until at least 12 years after baseline folate intake was determined (109188). A meta-analysis of observational studies suggests that the benefits of folic acid supplementation on colorectal cancer risk might be limited to patients with moderate to high alcohol consumption (110450). Other clinical evidence suggests that the beneficial effect of folic acid may be limited to colon, but not rectal, cancer (21501). Furthermore, the beneficial effect for colon cancer may be limited to only certain subtypes. For instance, females with folate intake of at least 400 mcg daily seem to have a 46% reduction in the risk of p53-overexpressing colon cancer, but not p53-negative tumors, when compared with those who consume less than 200 mcg daily (21300). Also, the source of folic acid may influence its effects. Some observational research suggests that dietary folate, but not folic acid supplementation, reduces the risk of colon cancer (21501).
Congenital heart disease. It is unclear if oral folic acid prevents congenital heart disease. Details: The exact cause of congenital heart disease is unknown but is thought to be a combination of genetic and environmental factors. Population research has found that supplementation with folic acid or folic acid-containing prenatal vitamins during pregnancy is associated with up to a 40% lower risk of congenital heart defects in newborns (99373).
Dementia. It is unclear if oral folic acid is beneficial for the prevention or treatment of dementia. Details: While some preliminary research shows that folic acid might aid in the prevention and treatment of Alzheimer disease (13165,15270,50246,90374), two small clinical trials show that taking folic acid 15-20 mg daily for 10-12 weeks does not seem to improve cognitive function or the severity of dementia in patients with various forms of dementia, including vascular dementia, Lewy body dementia, probable Alzheimer disease, or dementia due to other causes (50062,50597).
Diabetes. Small clinical studies suggest that oral folic acid does not improve glycemic control. Details: Meta-analyses of small clinical trials in patients with type 2 diabetes show that folic acid does not reduce glycated hemoglobin (HbA1C) when compared with placebo (50528,109197). Another small clinical study in patients with diabetes who are stabilized on metformin and/or a sulfonylurea shows that taking folic acid 5 mg daily for 8 weeks does not affect HbA1C when compared with placebo (104917). The validity of this study is limited by its small size and lack of blinding. Conversely, a meta-analysis of clinical research shows that taking folate modestly reduces fasting blood glucose and insulin levels, as well as measures of insulin resistance, when compared with placebo or no intervention (109197). There was no clear relationship between these changes and the dose or duration of folate. However, the studies included in this analysis evaluated multiple patient populations; the effect of folate in patients with diabetes, specifically, is unclear. Beyond glycemic control, some research has assessed the impact of dietary folate intake on cardiovascular risk in patients with diabetes. An observational study in Chinese adults with type 2 diabetes has found that dietary intake of folate in the highest quartile is associated with 68% lower odds of developing cardiovascular disease, defined as a non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina, when compared with folate intake in the lowest quartile (110452). Folic acid has also been evaluated in gestational diabetes. A meta-analysis of 20 studies shows that serum and red blood cell (RBC) folate levels are higher in patients with gestational diabetes than without gestational diabetes. Subgroup analysis suggests that patients with gestational diabetes have higher serum and RBC folate levels in the second trimester than in those without gestational diabetes, while RBC folate levels in patients with gestational diabetes were higher in the first trimester than those without gestational diabetes. Overall, higher serum folate levels are associated with a slight increase in the odds of gestational diabetes when compared with lower serum folate levels (112107).
Diabetic neuropathy. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with diabetic neuropathy shows that taking a combination of B vitamins, including folic acid (L-methylfolate), vitamin B12 (methylcobalamin), and vitamin B6 (pyridoxal-5'-phosphate), for 24 weeks does not improve neural dysfunction based on vibration perception, but does seem to improve total neuropathy symptoms, when compared with placebo. These symptoms, which include both sensation and pain, decreased by 25% with the B vitamin combination, compared with only 15% in those taking placebo (90375).
Epilepsy. It is unclear if oral folic acid reduces seizure frequency. Details: A meta-analysis of preliminary clinical research shows that taking folic acid does not reduce seizure frequency in patients with epilepsy (50124). However, there is some speculation that folate deficiency might be linked to increased seizure frequency. A preliminary clinical study in folate-deficient children with epilepsy shows that taking folic acid 5 mg daily for 3 months reduces seizure frequency when compared to baseline, but not when compared with a control group that is not deficient in folate (99371).
Erectile dysfunction (ED). Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in males with mild erectile dysfunction, overweight or obesity, and normal to low androgen levels shows that taking a combination product containing folic acid 400 mcg, alpha-lipoic acid, myo-inositol, and apple (Sinopol Forte, Laborest) improves measures of erectile dysfunction when compared to baseline (111674). The validity of these effects is limited by the small sample size and the lack of a comparator group, and it is unclear if these effects are due to folic acid, other ingredients, or the combination.
Esophageal cancer. Higher dietary folate intake is associated with a lower risk of esophageal cancer. Details: One meta-analysis of observational research has found that higher levels of dietary folate are associated with a 34% lower risk of esophageal squamous cell carcinoma and a 50% lower risk of esophageal adenocarcinoma when compared with low levels of dietary folate (50208). Another meta-analysis of observational research has found that consuming high amounts of folate is associated with a 36% decrease in the odds of esophageal cancer when compared with lower dietary folate intake (100950).
Fenofibrate (Tricor)-induced hyperhomocysteinemia. Folic acid seems to attenuate increases in homocysteine in people taking fenofibrate. Details: A small open-label clinical trial in patients taking fenofibrate shows that adding folic acid 10 mg every other day might reduce elevated plasma homocysteine levels by up to 59% when compared with taking fenofibrate alone (9321).
Gastric cancer. It is unclear if oral folic acid reduces gastric cancer risk. Details: Observational research has found that taking folic acid reduces the risk of gastric cardia adenocarcinoma by 17% and the risk of noncardia gastric cancer by 33%, but does not reduce the risk of gastric cancer overall (50208). Also, a meta-analysis of 13 small clinical studies in patients with gastric precancerous conditions shows that taking folic acid 20-30 mg daily for 3-6 months improves gastric mucosal atrophy and intestinal metaplasia but does not seem to improve symptoms when compared with a control (110448). Whether these findings are associated with a lower risk of gastric cancer is unclear.
Gout. It is unclear if oral folic acid reduces the risk for gout. Details: An observational study has found that increased dietary folate intake is associated with a lower incidence of gout (50454).
Head and neck cancer. It is unclear if oral folic acid is beneficial for head and neck cancer prevention. Details: Population research has found that the highest intake of dietary folate is associated with a 50% reduced risk of head and neck cancer when compared with the lowest intake of folate. Each 100 mcg increase per day seems to reduce the risk by about 4% (96151).
Hearing loss. It is unclear if oral folic acid prevents hearing loss. Details: Low levels of serum folate seem to be a risk factor for sudden sensorineural hearing loss in adults (21283). Observational research in females has found that serum folate levels in the lowest quintile are associated with a 19% increased risk for hearing loss when compared with levels in the second quintile. Also, folate levels in the highest quintile are associated with a 12% lower risk of hearing loss when compared with the second quintile (109807). A clinical study in older adults from the Netherlands shows that taking folic acid 800 mcg daily for 3 years slows the decline of age-related low-threshold hearing loss when compared with placebo (15163). However, at the time of this study, folate enrichment of foods was not allowed in the Netherlands. As a result, baseline folate levels in this study population were about 50% lower than in the US population. The effect of folic acid supplementation in people with higher baseline folate levels is unclear.
Infertility. It is unclear if oral 5-methyltetrahydrofolate (5-MTHF) in combination with vitamin B6 and vitamin B12 is more beneficial than folic acid alone for increasing pregnancy rate in females undergoing assisted reproductive technology (ART). Details: Retrospective research from Italy suggests that taking 5-MTHF 400 mcg, vitamin B12 5 mcg, and vitamin B6 3 mg daily results in clinical pregnancy and live birth rates of approximately 60% and 49%, respectively, compared with 45% and 35% of those taking folic acid 400 mcg daily. A sub-analysis suggests that beneficial effects on pregnancy rates are limited to individuals aged less than 40 years (109189). The findings from this study are limited by its retrospective design. Also, it is unclear if these findings are generalizable to countries with folate fortification.
Kidney failure. It is unclear if oral folic acid is beneficial in patients with kidney failure. Details: Because hemodialysis removes folate from the body, there is concern that folate deficiency may cause complications in patients with kidney failure receiving hemodialysis. Observational research in Taiwanese patients with kidney failure undergoing hemodialysis has found that taking folic acid 5 mg daily for an average of 5.8 years is associated with a 31% lower risk of arteriovenous access thrombosis when compared with folic acid 5 mg weekly. However, daily folic acid supplementation was not linked to a lower risk of cardiovascular events, cancer, or mortality when compared with weekly folic acid (110120). Oral folic acid has also been evaluated in combination with other ingredients. A small, low-quality clinical study in adults with kidney failure undergoing regular hemodialysis shows that taking oral folic acid 30 mg daily with thiamine 90 mg daily for 96 weeks reduces overall mortality by 67% and improves cognitive scores by 31% when compared with no intervention (107724). It is unclear if these findings are due to folic acid, thiamine, or the combination.
Lometrexol toxicity. While oral folic acid might reduce lometrexol toxicity, intravenous folic acid does not seem to help. Details: In a phase I trial, intravenous folic acid 5-25 mg administered 1 hour or 3 hours prior to lometrexol 15-30 mg/m2 every 3 weeks does not seem to reduce cumulative lometrexol toxicity (2161). However, in a phase II study, taking oral folic acid 3 mg/m2 daily in addition to lometrexol 10 mg/m2 weekly seems to attenuate cumulative toxicity and improve its tolerability in cancer patients (104948).
Low birth weight. It is unclear if oral folic acid supplementation during pregnancy reduces the risk of a low birth weight. Details: Clinical research shows that supplementation with folic acid 200 mcg to 5 mg daily during pregnancy increases mean birth weight when compared with placebo (91307). Furthermore, some population research has found that pre- or peri-conception folic acid supplementation, usually 400 mcg daily, is associated with a reduced risk of a child born small-for-gestational age. However post-conception folic acid supplementation is not associated with reduced risk (91304,103983). An observational study in pregnant Chinese patients found that supplementation with folic acid is associated with a 20% lower odds of low birth weight when compared with no supplementation. This association was observed when folic acid was used both before conception and during pregnancy for at least 24 weeks or during pregnancy only for at least 12 weeks. Increased dietary folate intake was not linked to a lower risk of low-birth-weight infants (110446). However, other observational research has found no association between folic acid supplementation during pregnancy and the risk for small-for-gestational age births (110447).
Lung cancer. It is unclear if oral folic acid reduces lung cancer risk. Details: There does not appear to be a relationship between deficiency of folate and lung cancer (9454). However, consuming at least 130.4 mcg of folate per 1000 kcal daily seems to reduce the risk of lung cancer by 40% in former smokers when compared to those with lower dietary folate intake (50065).
Melanoma. It is unclear if oral folic acid reduces melanoma risk. Details: Population research has found that folic acid supplementation of 2-2.5 mg daily in combination with vitamin B6 and vitamin B12 is linked with a 53% reduced risk of melanoma (91312).
Metabolic syndrome. Although there is interest in using oral folic acid for metabolic syndrome, there is insufficient reliable information about the clinical effects of folic acid for this condition.
Nitrate tolerance. It is unclear if oral folic acid helps to prevent the development of tolerance to treatment with nitroglycerin. Details: Some clinical evidence suggests that taking folic acid 1 mg daily for 1 week does not prevent the development of nitroglycerin-induced endothelial dysfunction or tolerance in healthy individuals (50442). However, other research suggests that taking folic acid 10 mg daily for 1 week prevents nitric oxide synthase dysfunction caused by continuous nitroglycerin (9316).
Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral folic acid is beneficial for NAFLD. Details: A cross-sectional analysis suggests that adults with NAFLD have lower levels of serum folate and its major component 5-MTHF when compared with healthy controls. Additionally, adults with NAFLD seem to consume less supplementary and dietary folate when compared with healthy controls. Overall, serum folate levels are negatively associated with the risk of NAFLD, and inadequate folate intake is associated with an increased risk of NAFLD (112104).
Oral clefts. It is unclear if oral folic acid reduces the risk of oral clefts in infants. Details: Observational research has found that maternal folic acid supplementation is associated with an up to 49% reduced risk of cleft lip with or without cleft palate (50220,104921). Furthermore, a large clinical trial in pregnancies at-risk for oral cleft suggests that taking a higher dose of folic acid 4 mg from pre-conception until the end of the first trimester results in a similar oral cleft recurrence rate of 2.5%, compared with a 2.9% recurrence with a lower dose of folic acid (400 mcg). Both doses demonstrate a lower incidence of oral clefts when compared with historical rates of 6.3% (91322). Although there is speculation that genetic markers of folate status impact the effect of folic acid on orofacial cleft incidence, the current data do not show a relationship (104921).
Overall mortality. It is unclear if oral folic acid reduces the risk of overall mortality. Details: Observational research in US adults has found that dietary intake of folic acid in the highest quintile is associated with a 14% to 23% lower risk of all-cause mortality and a 41% to 47% lower risk of cardiovascular mortality when compared with the lowest quintile of dietary folic acid intake (110451).
Pancreatic cancer. It is unclear if oral folic acid reduces pancreatic cancer risk. Details: Consuming greater than 280 mcg daily of dietary folate is associated with a decreased risk of exocrine pancreatic cancer (9327). A meta-analysis of case-control and cohort studies suggests that consuming higher amounts of dietary folate reduces the risk of pancreatic cancer by 51% compared to low levels of dietary folate (50208). However, another meta-analysis of prospective cohort studies suggests that folate/folic acid intake does not significantly affect the overall risk of pancreatic cancer (50499). The contradictory results may be associated with the form of intake or may be related to the gender of the participants. A meta-analysis of clinical research shows that dietary folate, but not folic acid, significantly reduces the risk of pancreatic cancer (50387). Also, one meta-analysis of observational studies has found that high dietary folate decreases the risk of pancreatic cancer in females, but not males (50387).
Peripheral neuropathy. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows taking a combination of folic acid 400 mcg, vitamin B12 3 mcg, and uridine monophosphate 50 mg daily (Keltican) for 60 days reduces pain associated with peripheral neuropathy. Use of this product reduces pain intensity by approximately 44%, with loss of burning pain in approximately 50% of patients, strong tingling or pricking in approximately 57% of patients, strong pain attacks in 92% of patients, and numbness in 90% of patients when compared with baseline. Radiating pain and the use of concomitant medications are also reduced (90384). The validity of this finding is limited by the lack of a comparator group. Furthermore, it is unclear if the benefits are due to folic acid, other ingredients, or the combination.
Pharyngeal cancer. It is unclear if oral folic acid reduces pharyngeal cancer risk. Details: Population research has found that intake of folic acid and folate from natural, fortified, and supplemented sources, may protect against oropharyngeal cancer. Intake of at least 258-816 mcg total folate/folic acid reduces the odds by 35% when compared with intakes of less than 344 mcg. Furthermore, folate/folic acid may be more beneficial for oral cancer versus pharyngeal cancer and in heavy alcohol users versus non users or light users (91302).
Polycystic ovary syndrome (PCOS). It is unclear if oral folic acid is beneficial for PCOS. Details: One clinical study in overweight or obese patients with PCOS shows that taking folate 1 mg or 5 mg daily for 8 weeks modestly reduces levels of homocysteine, as well as insulin resistance, when compared with placebo. However, only the 5 mg dose modestly reduces insulin, total cholesterol, and low-density lipoprotein (LDL) cholesterol levels. Neither dose appears to affect fasting plasma glucose, high-density lipoprotein (HDL) cholesterol, or triglyceride levels when compared with placebo (109200). Other clinical research in patients with PCOS taking metformin shows that taking folate 400 mcg daily for 6 months does not affect glycemic parameters, plasma lipid levels, or hormone levels when compared with placebo (109194). The reasons for discrepancies between studies are unclear but may relate to patient characteristics. One study included only overweight or obese individuals with at least two of the three PCOS criteria, whereas the other study limited enrollment to patients in any weight category but with all three PCOS criteria (109194,109200).
Pregnancy-induced hypertension. It is unclear if oral folic acid reduces the risk of hypertension during pregnancy. Details: Population research has found that taking folic acid during pregnancy is not associated with a reduced risk of gestational hypertension (91308,99370,99372).
Restless legs syndrome (RLS). Although there is interest in using oral folic acid for RLS, there is insufficient reliable information about the clinical effects of folic acid for this condition.
Schizophrenia. Oral folic acid 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 folic acid 2 mg and vitamin B12 400 mcg daily for 16 weeks improves negative symptoms when compared with placebo in patients with schizophrenia who have persistent symptoms and a specific genetic variant of the folate transporter gene FOLHI. This variant normally results in reduced folate absorption. However, in patients without this genetic variant, folate is not beneficial with respect to negative symptom improvement (90387).
Sickle cell disease. Oral folic acid has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B12 4.2-6 mcg, folic acid 700 mcg, and vitamin B6 4.2-6 mg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
Suicidal ideation. It is unclear if oral folic acid reduces the risk of suicidal ideation or suicide attempts. Details: One observational study has evaluated the association between folic acid supplementation and suicidal events in patients with various underlying conditions, including 12% with depression, 15% with anxiety, and 46% with pain. This within-person cohort study found that filling a prescription for folic acid 0.4-5 mg daily, either alone or as part of a multivitamin, is associated with a 44% reduced rate of suicidal events during the months after the prescription when compared with the months without the prescription. For the 48% of patients who received folic acid 1 mg daily, each additional month of taking the prescription was associated with a 5% decrease in suicidal events (109201). Prospective clinical research is needed to confirm any benefits of folic acid and to determine whether baseline folate deficiency plays a role in these outcomes. More evidence is needed to rate folic acid for these uses.

Aging skin. Although there has been interest in using topical Fucus vesiculosus for aging skin, there is insufficient reliable information about the clinical effects of Fucus vesiculosus for this purpose.
Cardiovascular disease (CVD). Although there has been interest in using oral Fucus vesiculosus for CVD, including atherosclerosis and hypertension, there is insufficient reliable information about the clinical effects of Fucus vesiculosus for this purpose.
Constipation. Although there has been interest in using oral Fucus vesiculosus for constipation, there is insufficient reliable information about the clinical effects of Fucus vesiculosus for this purpose.
Diarrhea. Although there has been interest in using oral Fucus vesiculosus for diarrhea, there is insufficient reliable information about the clinical effects of Fucus vesiculosus for this purpose.
Dyspepsia. Although there has been interest in using oral Fucus vesiculosus for dyspepsia, there is insufficient reliable information about the clinical effects of Fucus vesiculosus for this purpose.
Hypercholesterolemia. It is unclear if oral Fucus vesiculosus is beneficial in hypercholesterolemia. Details: A small clinical study in patients with obesity or overweight and low-density lipoprotein (LDL) cholesterol levels exceeding 77 mg/dL shows that taking a polyphenol-rich extract of Fucus vesiculosus (Maritech Synergy, Marinova) 2000 mg, providing 560 mg of polyphenols, daily for 12 weeks increases levels of high-density lipoprotein (HDL) cholesterol by 10%, compared with 2% in those receiving placebo. No differences were observed for total cholesterol, LDL cholesterol, or triglycerides (106723).
Hypothyroidism. Although there has been interest in using oral Fucus vesiculosus for hypothyroidism, there is insufficient reliable information about the clinical effects of Fucus vesiculosus for this purpose.
Impaired glucose tolerance (prediabetes). Oral Fucus vesiculosus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with prediabetes and dysglycemia shows that taking a specific product (Gdue, Aesculapius), containing extracts of Fucus vesiculosus and Ascophyllum nodosum in a 5:95 ratio along with chromium picolinate three times daily for 6 months reduces fasting and postprandial blood glucose, glycated hemoglobin (HbA1c), insulin, and insulin resistance when compared with placebo (100847). It is unclear if these effects are due to Fucus vesiculosus, other ingredients, or the combination. Another small clinical study in adults with prediabetes and also overweight or obese shows that taking a specific product (InSea2, InnoVactiv Inc.) containing 500 mg of Fucus vesiculosus and Ascophyllum nodosum extracts daily for 12 weeks reduces postprandial blood glucose but does not improve fasting blood glucose, HbA1c, body weight, lipids, or blood pressure when compared with placebo (110560).
Iodine deficiency. Although there has been interest in using oral Fucus vesiculosus for iodine deficiency and goiter, there is insufficient reliable information about the clinical effects of Fucus vesiculosus for this purpose.
Metabolic syndrome. Oral Fucus vesiculosus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research in adults with one or more components of metabolic syndrome has found that taking a specific combination product (Gdue, Aesculapius) containing extracts of Fucus vesiculosus and Ascophyllum nodosum in a 5:95 ratio along with chromium picolinate two to three times daily with meals for around 6 months is associated with reductions in body weight by 7.3 kg, waist circumference by 7.5 cm, fasting blood glucose by 16 mg/dL, glycated hemoglobin (HbA1c) by 0.55%, systolic blood pressure by 7 mmHg, diastolic blood pressure by 4 mmHg, low-density lipoprotein (LDL) cholesterol by 18 mg/dL, and 10-year cardiovascular risk scores by 1.8% when compared to baseline (110559). It is unclear if these effects are due to Fucus vesiculosus, other ingredients, or the combination. Further, the validity of these findings is limited by a lack of control group.
Obesity. Oral Fucus vesiculosus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in moderately overweight females shows that seaweeds such as Fucus vesiculosus, taken in combination with lecithin and vitamins for up to 2 years, do not result in sustained weight loss when compared to baseline (13663). Another small clinical study in adults with prediabetes and also overweight or obese shows that taking a specific product (InSea2, InnoVactiv Inc.) containing 500 mg of Fucus vesiculosus and Ascophyllum nodosum extracts daily for 12 weeks does not reduce body weight, body mass index (BMI), body fat, lipids, blood pressure, or measures of glycemic control when compared with placebo (110560).
Wound healing. Although there has been interest in using topical Fucus vesiculosus for wound healing, there is insufficient reliable information about the clinical effects of Fucus vesiculosus for this purpose. More evidence is needed to rate Fucus vesiculosus for these uses.

Atherosclerosis. When used alone or in combination with other ingredients, oral garlic seems to slow the progression of atherosclerosis. Details: Taking low doses of garlic powder (Kwai, Lichtwer Pharma) 300 mg, administered as a single dose or three times daily for up to 4 years, seems to lessen age-related decreases in aortic elasticity (4797,51595). Additionally, taking a specific time-released garlic powder supplement (Allicor, INAT-Farma) 150 mg twice daily for 24 months seems to reduce the rate of atherosclerosis progression, as measured by carotid intima-media thickness, when compared with placebo in males with early evidence of carotid atherosclerosis (88394). Higher doses of 900 mg daily seem to slow development of atherosclerosis in both aortic and femoral arteries when used over a four-year period in females, but not in males (3315,4798). In patients with evidence of coronary artery calcium and a Framingham risk score of greater than 10%, taking aged garlic extract (Kyolic Reserve, Wakunaga) 1200 mg twice daily for 12 months reduces coronary artery calcium progression by 29% when compared with placebo (102670). A meta-analysis also found that garlic powder tablets and aged garlic extract may reduce coronary artery calcium scores when compared with placebo (110721). Some clinical research has investigated the use of garlic in combination with other ingredients. Taking a specific supplement (Kyolic, Total Heart Health, Formula 108, Wakunaga) containing aged garlic extract 250 mg plus vitamin B12 100 mcg, folic acid 300 mcg, vitamin B6 12.5 mg, and L-arginine 100 mg daily for 12 months significantly reduces coronary artery calcium progression and improves vascular function in patients with a Framingham risk score of 10% to 20% without coronary artery disease (88385). In addition, taking a combination product containing aged garlic extract 1200 mg and coenzyme Q10 120 mg daily for one year significantly improves vascular elasticity endothelial function in firefighters facing high degrees of occupational stress (44225).
Diabetes. Most clinical research suggests that oral garlic, taken alone or in combination with metformin for at least 12 weeks, modestly reduces fasting blood glucose levels in patients with diabetes. It is unclear if garlic improves postprandial glucose levels or glycated hemoglobin (HbA1c). Details: A meta-analysis of results from seven clinical studies in adults with type 2 diabetes shows that taking garlic powder 600-1500 mg daily, garlic oil 8.2 mg daily, or aged garlic extract 1000 mg daily reduces fasting blood glucose levels by about 2 mg/dL when compared with control. The greatest benefit is seen for patients with hyperglycemia at baseline, for interventions lasting at least 12 weeks, and for formulations consisting of garlic powder (96004). Specific garlic formulations used in the reviewed studies have included garlic powder 300 mg 2-3 times daily as tablets (Kwai, Lichtwer Pharmaceuticals) or time-released tablets (Allicor, INAT-Farma) for 4-24 weeks, sometimes in combination with metformin or a sulfonylurea (51396,51463,96004). In one study, when used in combination with metformin, garlic reduced fasting blood glucose levels 70% more than when metformin was used alone (51463). The findings from these studies are in contrast with the results from older meta-analyses, which showed that garlic does not improve glycemic indices or lipid levels in patients with diabetes. Reasons for these discrepancies may relate to the fact that the older analyses included lower quality research (6465,6897). There is insufficient reliable information available to determine if garlic significantly improves postprandial glucose levels or HbA1c (96004). A small clinical trial shows that taking aged garlic extract (Kyolic, Wakunaga) 2400 mg daily for 12 months does not reduce left ventricular myocardial mass, a marker of poor cardiac outcomes, in patients with diabetes. However, this study may have been inadequately powered to detect a difference between groups (102671).
Endometriosis. Oral garlic seems to improve pain in people with endometriosis. Details: A clinical study in patients with endometriosis shows that taking a tablet containing garlic powder 400 mg, providing allicin 1.1 mg, daily for 3 months along with standard care reduces overall pain scores from baseline by 72%, compared with an increase of 4% from baseline in patients receiving placebo along with standard care (106615).
Hyperlipidemia. Most research shows that taking oral garlic for at least 8 weeks seems to modestly reduce total and low-density lipoprotein (LDL) cholesterol levels in patients with hyperlipidemia. However, evidence is conflicting on whether garlic improves high-density lipoprotein (HDL) cholesterol or triglyceride levels. Details: A robust meta-analysis on this topic suggests that, on average, garlic preparations reduce total cholesterol by 15 mg/dL and LDL cholesterol by 6 mg/dL when compared with placebo in patients with hyperlipidemia. These improvements appear to be more pronounced when garlic is taken for more than 8 weeks and in patients with total and LDL cholesterol levels that are at least borderline high before treatment. This same analysis shows no reduction in triglycerides and only a slight increase in HDL of 1.5 mg/dL with garlic treatment (88399). A more recent meta-analysis supports prior findings that taking garlic improves HDL, LDL, and apolipoprotein-A levels while having no impact on triglycerides level. The meta-analysis found that while garlic does not appear to reduce cholesterol in the general population, it may reduce total cholesterol when taken by patients with cardiovascular risk factors (110721). Another partially conflicting meta-analysis found that garlic powder reduces total cholesterol, LDL, and triglyceride levels, but has no impact on HDL levels (110720). The majority of available research supports these findings, but conflicting results exist (279,731,732,1873,1875,4782,4783,4784,4785,4786)(4787,4788,4789,4792,4793,4794,4795,4807,6457,6897)(51343,15295,15296,51422,51429,51469,51590,88399,107238)(107352,110721). Whether garlic is beneficial for treating hyperlipidemia may also depend on the specific formulation or product taken. Mixed results have been reported for a variety of specific garlic products, including garlic powder tablets (Kwai, Lichtwer Pharma) 600-900 mg daily in two or more divided doses for 6-16 weeks (279,731,4782,4783,4784,4785,4787,4789,4792,4793)(4795,4807), aged garlic extract (Kyolic, Wakunaga) 1000-7200 mg daily in divided doses for 4-6 months (1873,1875,15295), a garlic powder product (Garlex, Bosch Pharmaceuticals) 300 mg twice daily for 12 weeks (51343), aged back garlic extract (ABG+; PharmActive Biotech Products) 250 mg daily for 6 weeks (108607), and others (732,15295). Subgroup analyses from the most robust meta-analysis to date suggest that products containing aged garlic extract may be more effective for lowering total cholesterol than garlic powder preparations. If garlic powder preparations are used, total cholesterol levels seem to be lowered to a greater degree in patients taking enteric-coated garlic powder tablets. The opposite trend may be true for reducing LDL cholesterol. Garlic powder tablets seem to reduce LDL cholesterol levels while aged garlic extract does not. However, the few studies that did evaluate the effect of aged garlic extract on LDL cholesterol did so in patients with low baseline LDL cholesterol levels. There is limited evidence on the use of raw garlic or garlic oil products for treating hyperlipidemia (88399). Taking garlic 1200 mg with fish oil 3 grams daily for 4 weeks or garlic oil 500 mg with fish oil 700 mg daily for 60 days also appears to improve lipid parameters in some patients (4789,4790,51669). Garlic alone may be more effective than garlic plus fish oil for improving LDL cholesterol levels, but the combination may be useful in patients with elevated levels of total cholesterol, LDL cholesterol, and triglycerides (4789).
Hypertension. Some clinical research suggests that oral garlic seems to modestly reduce blood pressure in hypertensive and normotensive patients. Details: One meta-analysis of clinical studies show that taking garlic can reduce systolic and diastolic blood pressure by about 5 mmHg and 3 mmHg, respectively, in patients with or without hypertension (16605,51414,96007). However, another meta-analysis found that taking garlic may not impact systolic or diastolic blood pressure in patients with coronary artery disease when compared with placebo (110721). When only patients with hypertension are considered, taking garlic can decrease systolic blood pressure by about 7-9 mmHg and diastolic blood pressure by about 4-6 mmHg. These results are limited by the fact that many of the included studies were of low to moderate quality and short duration (96007,96008,96014). Most clinical research appears to support these findings (278,279,1873,51442,88398). However, conflicting results exist (107238,110721). Some garlic formulations evaluated for hypertension have included a specific garlic powder formulation (Kwai, Lichtwer Pharma) 2400 mg as a single dose or 600 mg daily for 12 weeks and a specific aged garlic extract (Garlic High Potency Everyday Formula 112, Wakunaga/Wagner) 960 mg to 7.2 grams daily in up to three divided doses for up to 6 months (278,279,1873,51442,88398). Other doses used in the available research have included garlic tablets 300-1500 mg in divided doses daily for 24 weeks (88386) and garlic oil 500 mg plus fish oil 600 mg daily for 60 days (51669). Hypotensive effects of garlic have also been examined in population research. A large population study found that eating raw garlic at least twice daily is associated with a reduced likelihood of having prehypertension when compared with eating raw garlic three or fewer times per week. However, any significant relationship was eliminated after adjusting for dietary salt, making conclusions difficult (102677).
Nonalcoholic fatty liver disease (NAFLD). Oral garlic seems to reduce the severity of hepatic steatosis in patients with NAFLD. Details: A meta-analysis including 4 studies with 186 patients with NAFLD found that taking 800-1600 mg of garlic powder daily may reduce aspartate aminotransferase (AST) and alanine transaminase (ALT) and lower the probability of hepatic steatosis by 2.75 times when compared with placebo (110720). Clinical research in patients with NAFLD shows that taking garlic powder reduces the severity of steatosis in 51% to 62% of patients, compared to 16% to 26% of those taking placebo (102681,103470). Doses of garlic included a specific powder (Amin Pharmaceutical Company) 800 mg twice daily for 12 weeks or an enteric-coated powder 400 mg twice daily for 15 weeks (102681,103479). There was also an improvement in most liver enzymes, other than alkaline phosphatase, and the level of low-density lipoprotein (LDL) cholesterol when compared with placebo (102681). In addition, population research shows a 7% reduction in odds of developing NAFLD with each 1 gram of raw garlic per 1000 kcal consumed. However, this association was not observed in females (102673). NAFLD is strongly and independently associated with an increased risk for prehypertension and hypertension. A clinical study in adults with NAFLD and stable diet- or antihypertensive-controlled blood pressure shows that taking an enteric-coated tablet containing garlic powder 400 mg (Amin Pharmaceuticals), providing allicin 1.5 mg, twice daily for 15 weeks reduces systolic blood pressure, diastolic blood pressure, and mean arterial pressure by 8, 3, and 6 mmHg, respectively, when compared with placebo. High-sensitivity C-reactive protein is also reduced by 16% when compared with placebo (106614).
Periodontitis. Oral aged garlic extract seems to improve some measures of gum health in people with mild to moderate periodontitis. Details: Clinical research in otherwise healthy patients with mild to moderate periodontitis shows that taking a specific aged garlic extract (Kyolic, Wakunaga) orally 1200 mg twice daily for 18 months improves probing pocket depth, but not gingival recession, when compared with placebo (105760). The validity of these findings is limited by the lack of an intention to treat analysis.

Gastric cancer. Oral garlic does not seem to prevent gastric cancer. Details: Clinical research evaluating the effects of taking aged garlic extract for 7 years failed to show a reduced risk of developing gastric cancer up to 22 years later (14447,51470,102016), although there was a reduction in mortality associated with gastric cancer in subjects followed for 12-22 years (5-15 years after stopping the garlic extract) (102016). Also, a prospective, case-control study of 123,484 adults over a 30-year review period suggests that garlic intake, whether obtained from the diet or via supplementation, is not associated with a reduction in the rate of gastric cancer occurrence (97034). However, some research disagrees. One prospective population study suggests that a 1 kg/year increased increment in garlic intake is associated with a 17% reduced risk in gastric cancer incidence over 22 years. Also, consuming at least 3.25 kg yearly is associated with at least a 12% reduced risk when compared with consuming less than 2 kg each year. A sub-analysis suggests that this potential benefit is associated with garlic stalks, rather than garlic bulbs (111764). Meta-analyses of population research, as well as small population studies, have suggested 23% to 51% lower odds of developing gastric cancer with increased dietary garlic intake when compared with never eating garlic (3320,4775,4776,51209,51460,96005,108604). However, these studies have limited external validity.
Helicobacter pylori. Oral garlic does not seem to be beneficial for Helicobacter pylori eradication. Details: Despite some promising initial laboratory research suggesting activity against Helicobacter pylori, garlic cloves, powder, or oil does not seem to have any beneficial effect when used to treat patients infected with Helicobacter pylori (3322,4761,4762,4763,4765,4774,97034).

Allergic rhinitis (hay fever). Although there has been interest in using oral garlic for allergic rhinitis (hay fever), there is insufficient reliable information about the clinical effects of garlic for this condition.
Alopecia areata. Topical garlic may increase hair growth by a small amount. Details: Preliminary clinical research in adults with alopecia areata shows that applying garlic 5% gel four times daily for 3 months, in addition to topical corticosteroid use, increases hair growth by 18% when compared with placebo plus topical corticosteroid (51386).
Asthma. Although there has been interest in using oral garlic for asthma, there is insufficient reliable information about the clinical effects of garlic for this condition.
Athletic performance. It is unclear if oral garlic is beneficial for athletic performance. Details: Preliminary clinical research shows that taking a single dose of garlic 900 mg prior to exercise increases endurance when compared with placebo in young athletes (51623). A small preliminary clinical trial shows that taking garlic extract 1000 mg daily for 4 weeks does not reduce the time to cycle 40 km when compared to placebo (111765).
Benign prostatic hyperplasia (BPH). It is unclear if oral garlic is beneficial for BPH. Details: In patients with BPH, preliminary clinical research shows that taking aqueous garlic extract 1 mg/kg daily for one month decreases prostate mass and urinary frequency and improves symptom scores and urinary flow rates when compared to baseline (10374). The validity of these findings is limited by the lack of a comparator group.
Bladder cancer. Although there has been interest in using oral garlic for bladder cancer, there is insufficient reliable information about the clinical effects of garlic for this condition.
Breast cancer. It is unclear if oral garlic prevents breast cancer. Details: The relationship between garlic intake and risk of breast cancer is unclear. Overall, population research suggests that taking garlic does not seem to decrease the risk of breast cancer. However, when garlic and onions are examined together, there is some evidence of an association with a decreased risk of breast cancer (4779,102674). More research is needed.
Bronchitis. Although there has been interest in using oral garlic for bronchitis, there is insufficient reliable information about the clinical effects of garlic for this condition.
Cardiovascular disease (CVD). It is unclear if oral garlic is beneficial for reducing CVD risk factors in adults with hypercholesterolemia. Details: A clinical crossover study in adults with moderate hypercholesterolemia shows that taking a specific product (ABG+; PharmActive Biotech Products) containing aged black garlic extract 250 mg, standardized to provide S-allyl-L-cysteine 1.25 mg, daily for 6 weeks does not improve blood pressure, glucose or cholesterol levels, or anthropometric measures when compared with placebo. A subgroup analysis in males with elevated diastolic blood pressure at baseline shows that taking this product reduces diastolic blood pressure by 5-mmHg when compared with placebo (108607). It is unclear if garlic is beneficial in patients with existing CVD.
Chronic fatigue syndrome (CFS). Although there has been interest in using oral garlic for CFS, there is insufficient reliable information about the clinical effects of garlic for this condition.
Colorectal cancer. It is unclear if oral garlic prevents colorectal cancer. Details: Several individual population studies have found that higher dietary intake of garlic is associated with a reduced risk of colorectal cancer (3320,4770,4771,4772). However, results from meta-analyses of population research are mixed (96003,102669). Reasons for the discrepancy seem to relate to the type of population study conducted. A meta-analysis of case-control studies supports a preventative effect of garlic. However, this is not supported when cohort studies are analyzed separately (102669). Case-control studies are prone to recall and selection bias, and some do not account for confounding factors associated with colorectal cancer (96003). Two separate meta-analyses of observational research conducted in various countries have found that consumption of garlic and other allium-containing vegetables (onions, leeks, chives and scallions) is associated with a reduced risk of colorectal cancer; however, subgroup analyses suggest improvement is greatest in studies conducted in Asian countries, modest in those conducted in North America, and absent in those conducted in Europe (108604,108605). The reasons for these differing findings are unclear but may be related to regional differences in dietary habits, such as the use of raw or cooked garlic. Few studies have examined the effects of garlic supplements. While a single preliminary clinical study in patients with confirmed colorectal adenomas shows that taking high-dose aged garlic extract 2.4 mL daily for 12 months reduces the risk of developing new adenomas by 29% when compared with a lower dose of 0.16 mL daily (51320), other studies do not support the use of garlic supplements for this purpose (4773,96003).
Common cold. Oral garlic might reduce the frequency of the common cold when used prophylactically. Details: Preliminary clinical research shows that taking one capsule of garlic daily for 12 weeks during the winter months reduces the number of self-reported colds by approximately 63% when compared with placebo. The duration of symptoms was also reduced by approximately one day (10787). Also, a small clinical trial in older patients living in residential care shows that 12% of those taking one capsule daily of a combination of garlic and onion powder (Aliocare, Domca Sau, Spain) for 36 weeks had one or more common cold episodes compared with 45% of those taking placebo. Each capsule provided 14 mg garlic powder (111768).
Corns. It is unclear if topical garlic is beneficial for corns. Details: Preliminary clinical research in a small number of patients with corns shows that applying a lipid soluble garlic extract topically to corns on the feet twice daily for 10-20 days results in improvement in most patients when compared with baseline (15030). The validity of this finding is limited by the lack of a comparator group.
Coronary heart disease (CHD). It is unclear if oral garlic is beneficial for CHD. Details: A meta-analysis of preliminary clinical research in adults with CHD shows that taking garlic orally 800-2000 mg daily for 2-48 weeks reduces total cholesterol levels by an average of 16 mg/dL when compared with placebo. Taking garlic did not affect other cholesterol levels; however, the study may have been inadequately powered to detect a difference between groups. The validity of this study is limited by inclusion of patients with and without dyslipidemia at baseline (107238).
Coronavirus disease 2019 (COVID-19). It is unclear if oral garlic is beneficial for COVID-19. Details: Clinical research in non-critically ill patients hospitalized with COVID-19 shows that taking garlic extract (Gallecina, Samisaz Pharmaceutical Company, Iran) 90 mg every 8 hours for 5 days or until discharge modestly reduces the proportion of patients requiring supplemental oxygen for at least 1 day when compared with placebo. However, there was no overall effect on clinical status, intensive care admission, or discharge prior to day 6. All patients also took remdesivir (111766). A small preliminary clinical study in patients hospitalized with mild to moderate symptoms of COVID-19 shows that taking garlic essential oil orally 50 mg twice daily before breakfast and dinner for 10 days, in addition to standard COVID-19 treatment, reduces the median duration of fever from 5 to 4 days, cough from 7 to 5 days, and weakness from 9 to 7 days when compared with standard treatment alone. The median time to a negative COVID-19 test decreased from 8 to 7 days (109530). The validity of this study is limited by incomplete randomization, the lack of a placebo comparator, and the exclusion of people with severe symptoms.
Cystic fibrosis. It is unclear if oral garlic is beneficial for cystic fibrosis. Details: Preliminary clinical research shows that taking garlic oil macerate 625 mg daily for 8 weeks does not improve pulmonary function, symptom scores, or the need for antibiotic therapy when compared with placebo in children with cystic fibrosis and chronic pulmonary infection (51438).
Dental hypersensitivity. Although there has been interest in using oral garlic for dental hypersensitivity, there is insufficient reliable information about the clinical effects of garlic for this condition.
Denture stomatitis. It is unclear if topical garlic as a mouthwash is beneficial for denture stomatitis. Details: Preliminary clinical research in patients with oral denture stomatitis shows that using a garlic mouthwash 40 mg/mL three times daily for 4 weeks improves redness when compared to baseline. When compared with nystatin, garlic has a lesser degree of recovery, but better patient satisfaction (51466).
Diabetic retinopathy. It is unclear if oral garlic is beneficial for diabetic retinopathy. Details: Preliminary research in patients with diabetic retinopathy and macular edema, treated with intravitreal bevacizumab and laser photocoagulation, shows that taking garlic powder 1 gram orally daily for 4 weeks improves the best-corrected visual acuity by 0.18 logMAR (logarithm of the minimum angle of resolution), compared with 0.06 for placebo. It also decreases intraocular pressure by 1 mmHg, compared with 0.3 mmHg for placebo (109529).
Diarrhea. Although there has been interest in using oral garlic for various types of diarrhea, including travelers' diarrhea and dysentery, there is insufficient reliable information about the clinical effects of garlic for these conditions.
Dysmenorrhea. Although there has been interest in using oral garlic for dysmenorrhea, there is insufficient reliable information about the clinical effects of garlic for this condition.
Esophageal cancer. It is unclear if oral garlic prevents esophageal cancer. Details: Observational research regarding the use of garlic in preventing esophageal cancer is conflicting. Some evidence suggests that raw garlic consumption does not prevent the development of esophageal cancer (51508). However, other population research suggests that weekly garlic consumption decreases the risk of developing esophageal cancer (51209).
Exercise-induced muscle soreness. It is unclear if oral garlic is beneficial for exercise-induced muscle soreness. Details: Preliminary clinical research shows that taking allicin, a constituent of garlic, 80 mg daily for 14 days can reduce subjective assessments of exercise-induced muscle soreness in athletes when compared with placebo (51404).
Fatigue. Although there has been interest in using oral garlic for fatigue, there is insufficient reliable information about the clinical effects of garlic for this condition.
Familial hypercholesterolemia. Oral garlic does not seem to improve blood lipid levels in children with familial hypercholesterolemia. Details: In children with familial hypercholesterolemia, a small clinical trial shows that taking garlic powdered extract, standardized based on alliin content, does not improve levels of total cholesterol, low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol, triglycerides, lipoprotein (a), apolipoprotein B-100, homocysteine, fibrinogen, or blood pressure (4796).
Fibrocystic breast disease. Oral garlic has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific combination product (Karinat, INAT-Farma), containing garlic powder 150 mg, beta-carotene 2.5 mg, alpha-tocopherol 5 mg, and ascorbic acid 30 mg twice daily for 6 months reduces the severity of breast pain, premenstrual syndrome, and menstruation pain, and can cause regression of palpable symptoms of breast fibromatosis (51317). It is unclear if these effects are due to garlic, other ingredients, or the combination.
Gastritis. Oral garlic has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with gastritis shows that taking a specific combination product (Karinat, INAT-Farma), containing garlic 150 mg, beta-carotene 2.5 mg, alpha-tocopherol 5 mg, and ascorbic acid 30 mg twice daily for 6 months improves digestion, inhibits H. pylori infection, and reduces the risk of precancerous lesion formation when compared with placebo (51308). It is unclear if these effects are due to garlic, other ingredients, or the combination.
Gout. Although there has been interest in using oral garlic for gout, there is insufficient reliable information about the clinical effects of garlic for this condition.
Hepatitis. It is unclear if oral garlic is beneficial for hepatitis. Details: Preliminary clinical research shows that taking 3-6 capsules of a product containing garlic oil 50 mg and diphenyl-dimethyl-dicarboxylate 25 mg per capsule daily for 6 weeks improves liver function enzyme levels when compared with placebo in patients with chronic hepatitis (51478). The effects of garlic alone have not been determined.
Hepatopulmonary syndrome. It is unclear if oral garlic is beneficial for hepatopulmonary syndrome. Details: Preliminary clinical research shows that garlic oil (Garlic Pearls, Ranbaxy, India) 1-2 grams/m² daily in two divided doses for 9-18 months may improve oxygen levels and remission rates when compared with placebo in patients with hepatopulmonary syndrome (51439).
Influenza. Oral garlic has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in older patients living in residential care shows that 12% of those taking one capsule daily of a combination of garlic and onion powder (Aliocare, Domca Sau, Spain) for 36 weeks had one or more influenza-like episodes compared with 36% of those taking placebo. Each capsule provided 14 mg garlic powder (111768).
Lead toxicity. It is unclear if oral garlic is beneficial for lead toxicity. Details: Preliminary clinical research shows that taking garlic powder 400 mg three times daily for 4 weeks reduces blood lead concentration when compared with baseline, but not when compared to treatment with D-penicillamine, in patients with mild to moderate lead poisoning (51467).
Lung cancer. It is unclear if oral garlic prevents lung cancer. Details: Some population research suggests that eating raw garlic is associated with a reduced odds of developing lung cancer. However, other research suggests that eating garlic or taking garlic supplements is not associated with a reduced risk of lung cancer (4778,103482). Reasons for the discrepancy possibly relate to the type of garlic consumed.
Metabolic syndrome. Small studies suggest that oral garlic may improve some metabolic parameters in patients with metabolic syndrome. Details: A clinical study in adults with metabolic syndrome shows that taking four tablets of garlic powder (Amin Pharmaceuticals), providing a total of 1600 mg garlic and 6 mg allicin, daily for 3 months improves waist circumference by 1.3 cm, blood pressure by 7-8 mmHg, HDL cholesterol levels by 4.5 mg/dL, and triglycerides levels by 40 mg/dL from baseline, compared with no improvement or worsening in patients taking placebo (106616). Similarly, preliminary clinical research in adults with metabolic syndrome shows that taking raw, crushed garlic 100 mg/kg twice daily for 4 weeks increases high-density lipoprotein (HDL) cholesterol and decreases waist circumference, blood pressure, triglycerides, and fasting blood glucose when compared to baseline (98812). The validity of these findings is limited by the lack of a control group. Another clinical study in adults with metabolic syndrome suggests that taking 1600 mg of garlic powder daily for 3 months may improve intestinal transit time, lipid accumulation product, cardiometabolic index, atherogenic index of plasma, and atherogenic indices including Castelli risk indices I and II (110722).
Mosquito repellent. It is unclear if oral garlic is beneficial as a mosquito repellent. Details: Preliminary clinical research shows that taking a single dose of garlic orally does not seem to effectively repel mosquitos (51322). The effect of long-term garlic administration is unclear.
Multiple myeloma. It is unclear if oral garlic prevents multiple myeloma. Details: A case-control study comparing a small population of adults with and without multiple myeloma has found that increased intake of garlic in the diet may be associated with a decreased risk of developing multiple myeloma (51476).
Muscle strength. It is unclear if oral garlic is beneficial for muscle strength. Details: Population research has found that increased consumption of raw garlic is associated with increased hand grip strength in healthy adults. Females consuming raw garlic 2-3 times per week were 23% less likely to have low handgrip strength, defined as being below the 20th percentile, when compared to those who almost never eat garlic. In males, the odds of having low handgrip strength were 34% lower. Eating any raw garlic, even less than once per week, was associated with an increased likelihood for having high grip strength (102678).
Obesity. It is unclear if oral garlic is beneficial for obesity. Details: Clinical research shows that taking garlic powder (Amin Pharmaceutical Company) 1600 mg daily for 12 weeks does not reduce body weight or body mass index when compared with placebo in overweight or obese patients with nonalcoholic fatty liver disease (NAFLD), although there is a small effect on waist circumference (102681). One small clinical study evaluating garlic in combination with multiple other ingredients shows that the combination (Prograde Metabolism) modestly improves body weight, fat mass, and waist and hip circumference when compared with placebo. The other ingredients include raspberry ketone, caffeine, capsicum extract, ginger root extract, bitter orange fruit, L-theanine, and black pepper fruit (40802). However, it is unclear if this benefit is due to garlic, other ingredients, or the combination.
Onychomycosis. Although there has been interest in using topical garlic for onychomycosis, there is insufficient reliable information about the clinical effects of garlic for this condition.
Oropharyngeal candidiasis. It is unclear if oral garlic is beneficial for oropharyngeal candidiasis. Details: Preliminary clinical research in patients with oral candidiasis shows that applying a topical garlic paste four times daily for 14 days to affected areas can increase the rate of complete eradication of oral lesions by 23% when compared with clotrimazole solution (51330).
Osteoarthritis. It is unclear if oral garlic is beneficial for osteoarthritis. Details: Preliminary clinical research in overweight and obese females with knee osteoarthritis shows that taking garlic tablets (Nature Made) 500 mg twice daily for 12 weeks modestly reduces pain scores by an additional 15% when compared with placebo (98813).
Otitis media. Although there has been interest in using topical garlic for otitis media, there is insufficient reliable information about the clinical effects of garlic for this condition.
Peripheral arterial disease (PAD). Oral garlic seems to improve pain-free walking distance by a small amount in patients with PAD. However, it does not seem to improve blood pressure. Details: In patients with stage II peripheral arterial occlusive disease, a small clinical trial shows that taking garlic (Kwai) 400 mg twice daily for 12 weeks improves pain-free walking distance by about 15 meters. There was no effect on blood pressure or ankle or brachial pressures (4801).
Polycystic ovary syndrome (PCOS). It is unclear if oral garlic is beneficial for PCOS. Details: Preliminary clinical research in adults with PCOS shows that taking garlic orally 800 mg daily for 8 weeks reduces low-density lipoprotein (LDL) cholesterol levels by approximately 8% when compared with placebo. Taking garlic did not affect other cholesterol levels; however, the study may have been inadequately powered to detect a difference between groups. Garlic supplementation also modestly reduces body mass index (BMI) and waist circumference in this population. However, there was no change in hip circumference (107238,111763).
Pre-eclampsia. It is unclear if oral garlic prevents pre-eclampsia during the third trimester. Details: Preliminary clinical research shows that taking a specific garlic extract (Garlet, Cosar Pharmaceutical Company) 800 mg daily during the third trimester of pregnancy does not reduce the risk of developing pre-eclampsia in high-risk patients with first-time pregnancies (9201,51626).
Premenstrual syndrome (PMS). It is unclear if oral garlic is beneficial for PMS. Details: Preliminary clinical research in adult students with moderate to severe PMS shows that taking a specific garlic supplement (Allium-S, Dineh Pharmaceutical Company) orally 400 mg daily, standardized to contain 1.1 mg allicin, for 3 menstrual cycles improves PMS symptom scores 1.4 times more than placebo. After taking garlic for 3 cycles, 91% of students improved to mild PMS, compared with only 36% in the placebo group (107239).
Prostate cancer. Observational research on the relationship between garlic intake and prostate cancer risk is conflicting. It is unclear if garlic supplements are beneficial in patients with prostate cancer. Details: Observational research in Chinese males shows that those who eat garlic 2.14 grams/day (about one clove) seem to have a 50% lower risk of developing prostate cancer (9876). Also, a pooled analysis of epidemiological research suggests that garlic consumption may be associated with a 23% decreased odds of developing prostate cancer (88410). A case-control study has also found that garlic, consumed at least twice weekly, may reduce the risk for prostate cancer when compared with lower consumption (4777). However, other population research suggests that garlic consumption has no effect on prostate cancer risk in Iranian males (51454). One very small clinical study in patients with prostate cancer shows that taking garlic extract 1 mg/kg daily for one month might improve prostate specific antigen (PSA) levels, urinary flow, and urinary frequency when compared with baseline (10374). The validity of these findings is limited by the small study size and lack of a comparator group.
Rheumatoid arthritis (RA). Oral garlic seems to reduce pain by a small amount in patients with RA. Details: Clinical research in females with RA shows that taking dried garlic (Garcin; Goldaru Co.) 500 mg twice daily, providing allicin 5 mg, for 8 weeks reduces pain after activity and improves functional ability by a small amount when compared with placebo. Fatigue and pain were reduced by approximately 13% and tender joint count was reduced by 47% (102680,103481). The long-term effect of garlic supplementation is unclear.
Scleroderma. It is unclear if oral garlic is beneficial for scleroderma. Details: Clinical research shows that taking garlic 900 mg daily for 7 days does not have an effect on vasomotor function when compared with placebo in females with scleroderma (51374).
Stress. Although there has been interest in using oral garlic for stress, there is insufficient reliable information about the clinical effects of garlic for this condition.
Tick repellent. It is unclear if oral garlic is beneficial as a tick repellent. Details: Preliminary clinical research shows that taking garlic 1200 mg daily for 8 weeks reduces the number of tick bites when compared with placebo (3318). However, the effect of garlic when compared with commercially available tick repellents is unknown (8027).
Tinea capitis. Although there has been interest in using topical garlic for tinea capitis, there is insufficient reliable information about the clinical effects of garlic for this condition.
Tinea corporis. It is unclear if topical garlic is beneficial for tinea corporis. Details: Applying a gel containing 0.6% ajoene, a constituent of garlic, twice daily for one week seems to be as effective as terbinafine 1% cream for tinea corporis (4767).
Tinea cruris. It is unclear if topical garlic is beneficial for tinea cruris. Details: Applying a gel containing 0.6% ajoene, a constituent of garlic, twice daily for one week seems to be as effective as terbinafine 1% cream for tinea cruris (4767).
Tinea pedis. It is unclear if topical garlic is beneficial for tinea pedis. Details: Applying a gel containing 1% ajoene, a constituent of garlic, twice daily seems to be more effective than 0.6% ajoene gel, and seems to be as effective as 1% terbinafine (Lamisil) for tinea pedis infections. Sixty days after completing one week of treatment, mycological cure occurred in 100% of patients using 1% ajoene, 72% of patients using 0.6% ajoene , and 94% of those using 1% terbinafine (8019). Additional research suggests that 0.4% ajoene gel twice daily has a 7-day cure rate of around 80% (4766).
Trichomoniasis. Although there has been interest in using oral garlic for trichomoniasis, there is insufficient reliable information about the clinical effects of garlic for this condition.
Tuberculosis. Although there has been interest in using oral garlic for tuberculosis, there is insufficient reliable information about the clinical effects of garlic for this condition.
Unstable angina. It is unclear if intravenous garlic is beneficial for unstable angina. Details: Preliminary clinical research in patients with unstable angina shows that giving garlicin, 60 mg by intravenous infusion daily for 10 days improves symptoms by 7% when compared with intravenous nitroglycerin (51244).
Urinary tract infections (UTIs). Although there has been interest in using oral garlic for UTIs, there is insufficient reliable information about the clinical effects of garlic for this condition.
Vaginal candidiasis. It is unclear if oral or topical garlic is beneficial for vaginal candidiasis. Details: One small clinical study in asymptomatic patients with culture-positive candida infections shows that taking garlic (Garlicin, Nature's Way) 1050 mg (3 tablets) twice daily for 14 days does not improve vaginal symptoms, candida colony counts, or cases of vaginal candidiasis when compared with placebo (88405). Another small clinical study shows that application of a vaginal cream containing garlic and thyme nightly for 7 nights is as effective as clotrimazole vaginal cream for treating vaginal candidiasis (88387). However, it is unclear if this effect is due to garlic, thyme, or the combination.
Warts. It is unclear if topical garlic is beneficial for warts. Details: Preliminary clinical research shows that applying a specific lipid-soluble garlic extract topically to warts on the hands twice daily results in wart resolution within 1-2 weeks. An aqueous garlic extract applied twice daily also seems to provide modest improvement, but only after 30-40 days of treatment (15030). The validity of these findings is limited by the lack of a comparator group.
Wound healing. It is unclear if topical garlic is beneficial for wound healing. Details: Based on patient and physician evaluations, preliminary clinical research shows that applying an ointment containing fresh garlic in petroleum jelly twice daily for 2 weeks results in 80% of surgical wounds healing at a faster rate than those treated with petroleum jelly. Most patients also indicated that the wound treated with garlic experienced less discomfort (102676). More evidence is needed to rate garlic for these uses.

Colic. Although there has been interest in using oral horseradish for colic, there is insufficient reliable information about the clinical effects of horseradish for this condition.
Gout. Although there has been interest in using oral horseradish for gout, there is insufficient reliable information about the clinical effects of horseradish for this condition.
Intestinal parasite infection. Although there has been interest in using oral horseradish for intestinal parasite infection, there is insufficient reliable information about the clinical effects of horseradish for this condition.
Respiratory tract infections. Oral horseradish root has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with a history of recurrent respiratory tract infections (RTIs) shows that taking a specific combination product (Angocin Anti-Infekt N, Repha GmbH) containing a total of 320-400 mg horseradish root and 800-1000 mg nasturtium daily for 12 weeks modestly decreases the rate of new RTIs when compared with placebo. However, there were no differences between groups in time to infection, intensity or duration of infection, or rates of specific infections, including acute rhinopharyngitis, sinusitis, laryngitis, or tracheitis (96309).
Urinary tract infections (UTIs). Oral horseradish root has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with recurrent UTIs shows that taking a specific product (Angocin Anti-Infekt N, Repha GmbH) containing a total of 320 mg horseradish root and 800 mg nasturtium daily for 90 days modestly reduces the recurrence of UTIs when compared with placebo at 3 months after treatment completion, but not at the time of treatment completion (96310). However, this analysis excluded patients that were not cured from their initial active UTI. Additionally, the small size, short duration, and high dropout rate in this study limits the validity of these findings. More evidence is needed to rate horseradish for these uses.

Bladder cancer. It is unclear if consuming kale in the diet can reduce the risk of bladder cancer. Details: Population research suggests that patients with bladder cancer consumed approximately 0.18 fewer cups of cruciferous vegetables, such as cabbage, Brussels sprout, cauliflower, broccoli, kale, or collards, on a weekly basis in the year prior to diagnosis when compared with people without bladder cancer. The effects of kale, specifically, are unclear (14864). Other population research suggests that eating at least five servings per week of cruciferous vegetables, such as cauliflower, Brussels sprout, cabbage, broccoli, and kale, is associated with a 51% reduction in the risk of developing bladder cancer in males when compared with eating up to one serving per week. However, higher intake of kale alone does not seem to be associated with a reduced risk of bladder cancer (26184).
Breast cancer. It is unclear if consuming kale in the diet can reduce the risk of breast cancer. Details: Population research suggests that the highest dietary intake of cruciferous vegetables, including broccoli, Brussels sprout, cabbage, cauliflower, collards, and kale, is associated with a slight increase in the risk of breast cancer in premenopausal adults when compared with the lowest intake (26188). Cruciferous vegetables might increase urinary levels of 2-hydroxyestrone, and its ratio to 16-alpha-hydroxyestrone, which could reduce the risk of breast cancer. However, research in pre-menopausal adults shows that taking a dried kale and Brussels sprout supplement, 3.3 grams daily for 8 weeks, or increasing dietary intake of Brussels sprout or broccoli by one 40-gram serving daily, does not increase urinary levels of 2-hydroxyestrone, or its ratio to 16-alpha-hydroxyestrone, when compared with placebo (112086). In postmenopausal adults, the highest intake of cruciferous vegetables appears to be associated with a statistically insignificant reduced risk of breast cancer (26188).
Inflammatory bowel disease (IBD). Although there is interest in oral kale for IBD, there is insufficient reliable information available about the use of kale for this purpose.
Menopausal symptoms. Although there is interest in oral kale for reducing menopausal symptoms, there is insufficient reliable information available about the use of kale for this purpose. More evidence is needed to rate kale for these uses.

Abortion. Despite traditional use for the induction of second trimester abortion, most research shows that intravaginal laminaria does not significantly reduce time to delivery or improve abortion rates, and it may actually worsen some outcomes when compared with standard of care. Details: One clinical study shows that intravaginal administration of laminaria along with misoprostol does not improve second trimester abortion rates at 24 and 48 hours after treatment initiation when compared with using only misoprostol. Also, using laminaria along with misoprostol does not shorten delivery time when compared with misoprostol alone (95688). Another small clinical study shows that adding intravaginal laminaria to misoprostol therapy significantly increases induction time and the need for opioid analgesics when compared with misoprostol alone (109576). Also, a small clinical study in patients undergoing second trimester abortions shows that intravaginal laminaria increases pain with cervical ripening and induction-to-delivery time when compared with mifepristone (109577). A retrospective study in 126 patients undergoing second trimester abortions has found that intravaginal administration of laminaria (Dilateria, Cooper Surgical) one day before using misoprostol might actually prolong delivery time by about 6 hours and does not improve abortion rates at 24 hours after induction when compared with misoprostol alone (105806). Some research shows that intravaginal administration of laminaria (Dilateria, Milex Products Inc.) one day before using prostaglandin E2 (PGE2) suppositories to induce second trimester abortions shortens the delivery time by about 3 hours when compared with PGE2 suppositories alone; however, the incidence of febrile episodes is about 2.3-fold higher for patients treated with laminaria (94045). Also, one small clinical study shows that intravaginal administration of laminaria the night before a scheduled abortion reduces procedure time by around 4 minutes, increases cervical dilation at the time of abortion, and reduces the need for additional dilation when compared with misoprostol treatment on the day of abortion. However, more patients preferred misoprostol over laminaria (109575). Laminaria has also been compared with a mechanical cervical dilation device, called Dilapan-S. A small clinical study in patients undergoing second trimester surgical abortion shows that intravaginal administration of laminaria for cervical preparation has no effect on pain scores or analgesic use following dilator placement or dilation and evacuation (D&E) when compared with Dilapan-S. The validity of these findings may be limited by the single-blinded nature of the study, as well as significant baseline differences between the treatment groups with respect to vaginal parity (105805).
Parturition. Intravaginal administration of laminaria does not seem to be beneficial for cervical ripening. Details: While some research suggests that intravaginal laminaria might reduce the duration of induction, results are conflicting. Additionally, studies suggest that intravaginal laminaria does not seem to reduce the incidence of birth by caesarean section (8945,95689,102765). Also, a small observational study has found that intravaginal laminaria is associated with a greater risk of endometritis and fetal infectious complications when compared with a control group not receiving laminaria (8945).

Acute radiation syndrome. Although there has been interest in using oral laminaria for acute radiation syndrome, there is insufficient reliable information about the clinical effects of laminaria for this purpose.
Cancer. Although there has been interest in using oral laminaria for cancer prevention, there is insufficient reliable information about the clinical effects of laminaria for this purpose.
Hypertension. Although there has been interest in using oral laminaria for hypertension, there is insufficient reliable information about the clinical effects of laminaria for this purpose.
Obesity. It is unclear if oral laminaria is beneficial in patients with obesity. Details: A small clinical study in overweight Japanese adults shows that taking iodine-reduced laminaria powder 2 grams, providing 1 gram of alginate, three times daily for 8 weeks reduces body fat percentage in males, but not females, when compared with placebo. Laminaria does not affect body weight or body mass index when compared with placebo (109572).
Radiation exposure. Although there has been interest in using oral laminaria to minimize environmental radiation exposure, there is insufficient reliable information about the clinical effects of laminaria for this purpose. More evidence is needed to rate laminaria for these uses.

LIPASE

Celiac disease. Although there has been interest in using oral lipase for celiac disease, there is insufficient reliable information about the clinical effects of lipase for this purpose.
Dyspepsia. It is unclear if oral lipase is beneficial for improving symptoms of postprandial distress syndrome. Details: A small clinical trial shows that taking a specific acid-resistant lipase (Amano Enzyme USA) 280 mg immediately before a high-fat meal does not reduce postprandial bloating and nausea when compared with placebo in individuals with postprandial distress syndrome (101900).
Inflammatory bowel disease (IBD). Although there has been interest in using oral lipase for IBD, there is insufficient reliable information about the clinical effects of lipase for this purpose.
Prematurity. It is unclear if adding a specific form of lipase, recombinant human bile salt-stimulated lipase (rhBSSL), to infant formula improves outcomes in premature infants. Some research suggests a potential increased risk for adverse effects. Details: Human breast milk contains rhBSSL, but it is inactivated when breast milk is pasteurized for donation. Clinical research in infants born before 32 weeks' gestation shows that adding rhBSSL as 8700 units per 100 mL formula or pasteurized breast milk, for 4 weeks does not increase growth velocity, body length, or head circumference over the next 12 months when compared with formula or pasteurized breast milk devoid of lipase. However, the infants who were small for gestational age (SGA), which made up approximately 15% of the study population, grew by an additional 1.9 grams/kg daily on average when compared with placebo (101940). More evidence is needed to rate lipase for these uses.

Coronary heart disease (CHD). A diet high in soluble fiber, such as that found in oats, reduces the risk of CHD. Details: Clinical research shows that a diet containing foods high in fiber, such as oats, oat bran, or whole oat flour, reduces the risk of CHD (2737,4960,4962,4963,4964,4965,4966,4967,4968). In 1993, the US Food and Drug Administration (FDA) approved a health claim stating that consuming at least 3 grams of soluble fiber per day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of CHD (102336). However, clinical studies show that at least 3.6 grams of soluble fiber daily is needed to reduce the risk of CHD (5786,5787,5788,5794,5795,5796).
Hypercholesterolemia. A diet rich in soluble fiber, such as that found in oats, can reduce cholesterol by a moderate amount. Details: Oats, oat bran, and other soluble fibers can modestly reduce total and low-density lipoprotein (LDL) cholesterol when consumed as part of a diet low in saturated fat. Consuming 56-150 grams of whole oat products such as oatmeal and oat bran, containing 3.6-10 grams of soluble fiber daily, can significantly lower total and LDL cholesterol levels. For each gram of soluble fiber consumed, total cholesterol decreases by about 1.4 mg/dL and LDL by about 1.2 mg/dL. Eating 3-10 grams of soluble fiber daily can reduce total cholesterol by about 4-14 mg/dL (4976,4977,5786,5788,5792,5794,5795,8521,107749); however, doses greater than 10 grams daily don't seem to increase effectiveness (5788). Eating three bowls of oatmeal (28 gram servings) daily can decrease total cholesterol by about 5 mg/dL (4972,4973,4974,4975,4976,4977,5786,5788,6188). Oat bran products, such as oat bran muffins and oat bran flakes, may vary in their ability to lower cholesterol, depending on the total soluble fiber content and other dietary variables (6188). Whole oat products might be more effective for lowering LDL and total cholesterol than foods containing oat bran plus soluble fiber (10145).

Diabetes. A diet rich in whole grains, such as oats, may help prevent diabetes or improve blood glucose control in patients with type 1, type 2, or gestational diabetes. Details: Population research shows that for every 16 gram daily serving of whole grains, including oats, there is a 7% to 11% lower risk of developing type 2 diabetes (100622). There is also evidence that consuming oats can decrease blood glucose and insulin levels, as well as lipid levels, in patients with diabetes. The glycemic effects of oats depend on the level of processing of the oat products. Consuming intact oat kernels or thick-cut oats (>0.6 mm) reduces postprandial blood glucose and insulin, but consuming thin-cut, or "quick", oats has no effect (105536). Clinical research shows that consuming oats and oat bran for 4-8 weeks decreases pre-prandial blood glucose, 24-hour plasma glucose, glycated hemoglobin (HbA1c), insulin levels, and low-density lipoprotein (LDL) cholesterol in people with type 2 diabetes (4980,4982,6266,103345). Various doses have been used, including 3 grams of soluble fiber daily, or bread providing 34 grams of total fiber daily (9 grams of soluble fiber) (4961,4980). Additional clinical research in obese adults with type 2 diabetes shows that eating whole grain oats 50-100 grams daily in place of other carbohydrates reduces postprandial blood glucose by 19-27 mg/dL when compared with other carbohydrates in a healthy diet. After 1 year, the groups consuming 50 grams and 100 grams of oats had an additional 0.48% and 0.64% reduction in HbA1c, respectively, when compared with the regular healthy diet group (97520). There is also some evidence that consuming oats 50 grams daily, containing 25 grams of soluble fiber, might be more effective for improving glycemic control and decreasing hyperinsulinemia than the standard moderate fiber diet recommended by the American Diabetes Association (ADA) (6266). Oats have also been evaluated in adolescents with type 1 diabetes. One very small clinical study shows that taking 50 grams of a specific oat product (Betaglucare), providing beta-glucans 6 grams, in three divided doses daily for one week is beneficial for glycemic control and variability when compared with a standard diet without beta-glucans or with taking only 25 grams of the product daily. Maximal, mean, and pre- and post-meal blood glucose levels were modestly lower, and minimal blood glucose levels were modestly higher. Most measures of glycemic variability were statistically different, although there were no differences in the duration of hypoglycemia or hyperglycemia between groups (105261). Oats have also been evaluated in patients with gestational diabetes. A randomized, controlled trial shows that taking 30 grams of a specific oat bran product (OAB; Golden Light Cup Company) orally twice daily at lunch and dinner for 4 weeks improves mean fasting blood glucose and two-hour postprandial glucose when compared with a control group. After 4 weeks, the mean fasting blood glucose and 2-hour postprandial glucose in the treatment group were 85 mg/dL and 104 mg/dL, respectively, compared with 93 mg/dL and 117 mg/dL, respectively, in the control group (107751). The validity of this study is limited by the short treatment duration and lack of follow-up.
Gastric cancer. A diet rich in soluble fiber, such as that found in oats, might reduce the risk of gastric cancer. Details: Observational research has found that consuming a diet that includes cereal fiber, such as oats and oat bran, might reduce the incidence of gastric cancer (10435).

Colorectal cancer. Regular consumption of oats does not seem to reduce the risk of colorectal cancer. Details: Observational research has found that consuming oat bran or oats orally doesn't seem to reduce the risk of colon cancer. Additionally, consuming fiber, including oat-bran fiber, is not associated with a reduction in the risk for recurrence of colorectal adenomas (4820,5104).

Acne. Although there is interest in using topical oats for acne, there is insufficient reliable information about the clinical effects of oats for this purpose.
Anxiety. Although there is interest in using oral oats for anxiety, there is insufficient reliable information about the clinical effects of oats for this purpose.
Atopic dermatitis (eczema). Topical colloidal oatmeal cream may be beneficial in patients with atopic dermatitis. Details: Preliminary clinical research shows that applying a cream containing colloidal oatmeal 1% daily for 2 weeks has a moderate effect on the severity of atopic dermatitis when compared with baseline (103344). The validity of this finding is limited by the lack of a comparator group. Other research suggests that colloidal oatmeal may be beneficial when used in combination with topical steroids. Clinical research shows that the benefits obtained from applying an ointment containing fluocinolone 0.025% to the hands for 2 weeks were better maintained in the patients who also used a cream containing colloidal oatmeal 1% during this time period and for an additional 4 weeks when compared with patients using fluocinolone and the cream base without colloidal oatmeal. Quality of life was also improved in the patients using colloidal oatmeal (103340).
Breast cancer. Observational research suggests that regular oatmeal intake may be associated with reduced mortality from breast cancer. Details: Population research in postmenopausal patients has found that those who have eaten 50 grams of oatmeal daily prior to a breast cancer diagnosis have a 20% reduced risk of all-cause mortality in the 7 years following the diagnosis when compared with patients who have not eaten oatmeal. However, no benefit was seen when post-diagnostic oatmeal intakes were examined (103343).
Burns. Although there is interest in using topical oats for burns, there is insufficient reliable information about the clinical effects of oats for this purpose.
Chronic fatigue syndrome (CFS). Although there is interest in using oral oats for CFS, there is insufficient reliable information about the clinical effects of oats for this purpose.
Cognitive function. It is unclear if oral oats are beneficial in healthy adults with mild memory impairment. Details: Preliminary clinical research in healthy middle-aged adults with self-reported memory decline shows that consuming a specific wild green-oats extract (Neuravena, Frutarom) 800 mg as a single dose improves overall speed, but not overall accuracy, of cognitive performance when compared with placebo. However, a higher dose of 1600 mg was ineffective (97519).
Dry skin. It is unclear if applying lotion containing colloidal oat extract improves dry skin to a greater extent than other lotion products. Details: Preliminary clinical research shows that applying a lotion containing colloidal oat extract (Aveeno Active Naturals Skin Relief 24Hr Moisturizing Lotion, Johnson & Johnson) twice daily for 2 weeks improves itchiness, cracking, scaling, dryness, and roughness when compared to baseline in females with dry skin (91458). Additional preliminary clinical research shows that applying a colloidal oatmeal lotion to the legs twice daily for three weeks reduces skin dryness and improves skin integrity when compared to baseline in adults with dry skin (97518). The validity of these findings is limited by the lack of a comparator group.
Exercise-induced muscle soreness. It is unclear if oral oats are beneficial for exercise-induced muscle soreness. Details: A small clinical trial shows that eating two cookies containing oat flour 60 grams daily for 8 weeks reduces muscle soreness 48 or 72 hours after downhill running when compared with baseline (103341).
Fat redistribution syndrome. It is unclear if oral oats are beneficial for fat redistribution syndrome. Details: Consumption of a high fiber diet, including oats, with adequate energy and protein might prevent fat deposition in patients with HIV. A one-gram increase in total dietary fiber may decrease the risk of fat deposition by 7% (12517).
Gallbladder disease. Although there is interest in using oral oats for gallbladder disease, there is insufficient reliable information about the clinical effects of oats for this purpose.
Hypertension. It is unclear if oral oats are beneficial for hypertension. Details: Observational research has found that consumption of oats as oatmeal or oat cereal does not seem to reduce diastolic blood pressure (DBP) or systolic blood pressure (SBP) in males with minor elevations in blood pressure (2956). A randomized, controlled trial in patients with stage 1 hypertension receiving dietary guidance shows that taking 30 grams of oat bran, providing 8.9 grams of dietary fiber, once daily with breakfast or in between meals for 3 months improves various blood pressure measures when compared with dietary guidance alone. After 3 months of treatment, 24-hour maximum SBP and DBP decreased by 14 mmHg and 11 mmHg, respectively, and office SBP and DBP decreased by 15 mmHg and 10 mmHg, respectively. Oat consumption may also have impacted antihypertensive medication use. Two patients in the control group increased doses of antihypertensive medications, whereas 6 patients in the treatment group decreased doses and 1 patient discontinued use (107750). The effect of oral oat bran on patients with stage 2 hypertension or pre-hypertension is unknown.
Irritable bowel syndrome (IBS). Although there is interest in using oral oats for IBS, there is insufficient reliable information about the clinical effects of oats for this purpose.
Metabolic syndrome. Limited research suggests that oats may not be beneficial for metabolic syndrome. Details: Preliminary clinical research in adults with metabolic syndrome shows that adding oat bran 40 grams daily for 6 weeks to a low-calorie diet does not reduce the incidence of metabolic syndrome. Oat bran also does not improve body weight, blood pressure, low-density lipoprotein (LDL) cholesterol, triglycerides, or blood glucose levels when compared with a low-calorie diet alone in patients with metabolic syndrome (103342).
Osteoarthritis. Although there is interest in using oral oats for osteoarthritis, there is insufficient reliable information about the clinical effects of oats for this condition.
Pruritus. Applying oat lotion topically may improve some types of pruritus. Details: Preliminary clinical research shows that applying an oat lotion (Espanol) twice daily for up to 2 weeks can decrease itching intensity by about 20% when compared to baseline in patients with pruritus associated with chronic kidney disease (uremic pruritus). This decrease is similar to the effects of applying vinegar 5% solution or taking hydroxyzine 10 mg orally. However, applying the oat lotion does not appear to decrease the frequency of itching (91457).
Psoriasis. Although there is interest in using topical oats for psoriasis, there is insufficient reliable information about the clinical effects of oats for this purpose.
Rheumatoid arthritis (RA). Although there is interest in using oral oats for RA, there is insufficient reliable information about the clinical effects of oats for this purpose.
Stroke. It is unclear if oral oats are beneficial for reducing the risk of stroke. Details: Population research suggests that consuming oatmeal for breakfast once weekly might reduce the incidence of stroke by a small amount when compared with consuming white bread or eggs for breakfast (103337).
Ulcerative colitis. Oral oats have only been evaluated in combination with other ingredients; their effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific oat-based product (Profermin, Nordisk Rebalance) containing fermented oat flour, Lactobacillus plantarum, barley malt flour, and lecithin, 250 mL orally twice daily for 8 weeks, reduces disease activity and increases remission in about two-fold more patients with relapsing ulcerative colitis, when compared with treatment with a specific nutritional beverage (Fresubin Original, Fresenius Kabi) (90271).
Wound healing. Although there is interest in using topical oats for wound healing, there is insufficient reliable information about the clinical effects of oats for this purpose. More evidence is needed to rate oats for these uses.

Scarring. Clinical research in adults and children shows that topical application of onion extract, often as part of combination products, for 10 weeks to 6 months is beneficial for preventing scarring; however, the most effective combination of ingredients, dosage form, and dose are unclear. Details: Many small clinical trials show that using topical onion extract improves the appearance, as well as pain and itching, associated with postburn hypertrophic scars, keloidal scars, scars following tattoo removal, scars following Cesarean delivery, or scars following surgical removal of tissue when compared with control (66895,66918,66939,66951,66987,67089,67104,95151,95156,95159,104773). Products evaluated in clinical research have included gels containing a combination of onion extract, heparin, and allantoin (Contractubex, Merz Pharmaceuticals) (66895,66987,67089,67104,104773); a combination of onion extract and a silicone derivative (Cybele scagel, Bangkok Botanica) (95156,95159); a combination of onion extract, allantoin, pentaglycan, and a solution of glycosaminoglycans (Kaloidon gel, Laboratori Farmacologici Milanesi) (95151); and a transdermal patch containing a combination of onion extract and allantoin (104771). However, not all research agrees. A meta-analysis of randomized controlled trials using onion extract gel for scar management demonstrated mixed results when compared with control. However, the validity of the study is limited by high heterogeneity (109511). In addition, a specific product containing onion extract and allantoin (Mederma, Merz Pharmaceuticals) for 4-11 weeks does not appear to improve the appearance of new surgical scars (66742,66883). Similarly, observational research has found that a topical patch containing onion extract and allantoin is not associated with improved provider- or patient-assessed appearance of scars following cesarean-delivery after 4 weeks when compared with those using no scar treatment (104771). It is possible that the duration of treatment in these studies was inadequate to identify improvement.

Obesity. Clinical research does not support the use of dietary onion or onion supplements for weight loss. Details: Clinical research in overweight patients shows that taking capsules containing steamed onion (Oniro, Kunpoong Bio Co., Ltd) 300 mg orally three times daily for 12 weeks does not reduce body mass index (BMI), fat distribution, or fat mass when compared with placebo (101747). In addition, one clinical study in overweight and obese patients with polycystic ovary syndrome (PCOS) shows that eating raw red onion 80-120 grams daily can actually increase BMI by 0.36 kg/m2 when compared with eating 20-30 grams of raw red onion (95155). Clinical studies have also used onion products standardized by quercetin content. Preliminary clinical research in overweight and obese patients shows that taking onion peel extract providing quercetin 100 mg orally daily for 12 weeks reduces body weight by up to 1.1 kg and BMI by up to 0.4 kg/m2 when compared to baseline, but not when compared with placebo (95152,101748). Another small clinical study in healthy, overweight Japanese adults shows that taking an onion powder containing quercetin 60 mg orally daily for 12 weeks does not reduce body weight, BMI, abdominal circumference, or abdominal fat when compared with the same quantity of quercetin-free onion powder (104772).

Alopecia areata. It is unclear if topical onion is beneficial in patients with alopecia areata. Details: Preliminary clinical research in children and adults with alopecia areata shows that topical application of raw onion juice twice daily for 8 weeks improves hair growth when compared with placebo. Hair regrowth was demonstrated in 74% of subjects using onion juice, compared with 13% using placebo (66797).
Angina. Although there has been interest in using oral onion for angina, there is insufficient reliable information about the clinical effects of onion for this purpose.
Asthma. Although there has been interest in using oral onion for asthma, there is insufficient reliable information about the clinical effects of onion for this purpose.
Atherosclerosis. Although there has been interest in using oral onion for atherosclerosis, there is insufficient reliable information about the clinical effects of onion for this purpose.
Bruises. Although there has been interest in using topical onion for bruises, there is insufficient reliable information about the clinical effects of onion for this purpose.
Diabetes. It is unclear if oral onion is beneficial in patients with diabetes. Details: Preliminary clinical research in adults with type 2 diabetes shows that taking fresh onion 20 grams orally three times daily, in addition to consuming a controlled diet, for 8 weeks decreases blood glucose levels by 5% when compared with a controlled diet alone (67072).
Dyspepsia. Although there has been interest in using oral onion for dyspepsia, there is insufficient reliable information about the clinical effects of onion for this purpose.
Gastric cancer. It is unclear if oral onion is beneficial for preventing gastric cancer. Details: Population research has found that the highest dietary intake of onion is associated with a 48% reduced odds of gastric cancer when compared with the lowest intake (51460).
Hypertension. It is unclear if oral onion is beneficial in patients with hypertension. Details: Preliminary clinical research in overweight or obese adults with prehypertension or hypertension shows that taking onion skin extract 132 mg orally three times daily for 6 weeks reduces 24-hour systolic blood pressure by 4 mmHg, but does not affect diastolic blood pressure, when compared with placebo (95149). Other preliminary clinical research in patients with hypertension shows that taking a specific product (Campo di mele formula, Phyt-Immun) containing onion 2.5 grams, olive oil 5 mL, grape skin extract 50 mg, L-carnitine 30 mg, vitamin E 3 mg, vitamin C 2 mg, lycopene 1 mg, and folic acid 44 mcg, once daily for one week, decreases systolic and diastolic blood pressure by 5 mmHg and 2 mmHg, respectively, when compared with placebo (66766). It is unclear if this effect is due to onion, other ingredients, or the combination.
Hypothyroidism. It is unclear if oral onion is beneficial for preventing hypothyroidism. Details: Population research in females has found that high dietary intake of onion is associated with a lower risk of subclinical hypothyroidism when compared with low dietary intake, However, this association was not identified in males. The association of dietary onion intake with symptomatic hypothyroidism was not evaluated (109512).
Insect bite. Although there has been interest in using topical onion for insect bites, there is insufficient reliable information about the clinical effects of onion for this purpose.
Insomnia. It is unclear if oral onion is beneficial in patients with poor sleep quality. Details: Preliminary clinical research in healthy adults that were unsatisfied with their current sleep quality shows that taking onion extract 500 mg orally three times daily for 5 days may slightly improve sleep latency and waking after sleep onset, but does not change self-rated sleep quality, when compared with placebo (104774).
Polycystic ovary syndrome (PCOS). It is unclear if oral onion is beneficial in patients with PCOS. Details: Clinical research in overweight or obese adults with PCOS shows that eating 80-120 grams of raw red onion daily does not improve levels of fasting blood glucose, cholesterol, triglycerides, or lipoprotein (a), and can increase body mass index (BMI) by 0.36 kg/m2, when compared with eating 20-30 grams of raw red onion daily (95155).
Prostate cancer. It is unclear if oral onion is beneficial for preventing prostate cancer. Details: Population research has found that high dietary intake of onion is not associated with a lower odds of developing prostate cancer when compared with low dietary intake of onion (88410).
Respiratory tract infections. Although there has been interest in using oral onion for respiratory tract infections, including the common cold, there is insufficient reliable information about the clinical effects of onion for this purpose.
Stretch marks (striae gravidarum). Topical onion has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adult females shows that applying a specific cream (Mederma For Stretch Marks, Merz Pharmaceuticals) containing onion extract, gotu kola, and hyaluronic acid to striae rubra twice daily for 12 weeks improves stretch mark scores, including color, softness, and texture, when compared with no treatment (95154).
Warts. Although there has been interest in using topical onion for warts, there is insufficient reliable information about the clinical effects of onion for this purpose. More evidence is needed to rate onion for these uses.

Melasma. Preliminary clinical research in adults with melasma shows that applying a brewed parsley water to the face with a cotton ball on 6 days of each week for 8 weeks is as effective as hydroquinone 4% cream for improving dark spots (96828). More evidence is needed to rate parsley for this use.

PHYTASE

Aging skin. In patients with deep wrinkles, preliminary clinical research shows that taking zinc citrate 50 mg and phytase 3,000 units daily for four days prior to a botulinum toxin treatment increases the patient-reported duration of botulinum toxin effects by approximately 25%, compared with no improvement in patients taking zinc gluconate 10 mg or placebo. The efficacy of botulinum treatment was also improved (101913). Whether this reported benefit is due to the dose or form of zinc, citrate, phytase, the combination, or other factors, is unclear (101913,101914).
Blepharospasm. In patients with blepharospasm, preliminary clinical research shows that taking zinc citrate 50 mg and phytase 3,000 units daily for four days prior to a botulinum toxin treatment increases the patient-reported duration of botulinum toxin effects by approximately 25%, compared with no improvement in patients taking zinc gluconate 10 mg or placebo. The efficacy of botulinum treatment was also improved (101913). Whether this reported benefit is due to the dose or form of zinc, citrate, phytase, the combination, or other factors, is unclear (101913,101914).
Child growth. Clinical research in infants consuming a corn-based diet shows that taking a fat- and micronutrient-based food supplement containing phytase, docosahexaenoic acid (DHA), arachidonic acid, and lysine increases linear growth at age 8 and 10 months and improves locomotor development when compared with not taking this supplement. In contrast, a similar fat- and micronutrient-based supplement without phytase, DHA, arachidonic acid, and lysine does not improve these indices when compared with not taking a supplement. The phytase-containing supplement did not affect linear growth, weight for age, or hand-eye coordination at 12 months (101902). These reported benefits to child growth are likely to be due to the combination of provided essential and non-essential nutrients. Any role of phytase is expected to be minimal.
Iron deficiency anemia. Taking phytase with a meal containing phytate and iron increases iron absorption (101903,101904,101906). However, the effect of phytase specifically for the treatment of iron deficiency anemia remains unclear (101902). Phytase is sometimes added to the diet to increase the absorption of iron from food. In a small study of women, some with iron deficiency anemia, incubating wheat as a source of phytase with a traditional grain high in phytate increased iron absorption from the meal to 8.3% from 2.6% (101904). Also, adding microbial phytase to whole wheat rolls containing phytate increases iron absorption from a meal by approximately 82% when compared with rolls without added phytase (101906). In another small study, the addition of a microbial phytase to a single corn meal with added micronutrients increases iron absorption and incorporation into red blood cells after 14 days by 1.85-fold when compared with the meal without added phytase (101903). However, consuming white wheat rolls with added wheat bran as a source of phytase does not increase iron absorption from the meal when compared to consuming rolls with added wheat bran with deactivated phytase (101906). The use of phytase as treatment for iron deficiency, with or without anemia, has rarely been investigated. However, clinical research in infants consuming a corn-based diet shows that taking a fat- and micronutrient-based food supplement containing phytase, docosahexaenoic acid (DHA), arachidonic acid, and lysine for 6 months does not seem to be more effective for reducing anemia than taking the food supplement without phytase (101902).
Zinc deficiency. Preliminary clinical research shows that adding phytase 20.5 units to a millet-based porridge with added zinc immediately prior to consumption increases zinc absorption by approximately 68% in children aged 12-24 months (101911). Some of these children had low plasma levels of zinc at baseline. However, the use of phytase specifically for the treatment of zinc deficiency has not been investigated. More evidence is needed to rate phytase for these uses.

Proteolytic enzymes represent a wide group of enzymes that are used alone or in combination. See specific monographs for effectiveness information.

Benign prostatic hyperplasia (BPH). Taking oral pumpkin seed or pumpkin seed oil may improve symptoms of BPH. Details: One study in patients with BPH shows that taking pumpkin seed 5 grams twice daily for 12 months may be more effective for controlling symptoms than pumpkin seed extract 1000 mg twice daily (92383). A specific pumpkin seed extract (Prosta Pink Forte) 1-2 capsules daily for 12 weeks has also been used (11231). Some preliminary clinical research also suggests that taking pumpkin seed oil (Prostafit, EuRho Vital) two tablets daily for 6 months may be as effective as the medication prazosin (92382). Pumpkin seed oil has also been compared with tamsulosin. A clinical study comparing pumpkin seed oil 360 mg twice daily to tamsulosin 0.4 mg once nightly for 3 months shows that both treatment groups report improvements in BPH symptoms and quality of life when compared with baseline, although improvement appears greater in the tamsulosin group, specifically when measured at 1 month and 3 months. In the pumpkin seed oil group, adverse effects were reported in 0% of patients, compared with 15% of patients taking tamsulosin (107842). The validity of this study is limited due to the short duration of treatment. Pumpkin seed oil or extracts have also been studied in combination with saw palmetto (6777), with saw palmetto, nettle root, and lemon extracts plus beta carotene (5093), and with saw palmetto, small flowered willow herb, lycopene, and pygeum (92379).

Androgenic alopecia. Oral pumpkin seed oil might improve hair regrowth in males with mild to moderate hair loss. Details: Clinical research in males with mild to moderate hair loss shows that taking pumpkin seed oil (Octa Sabal Plus, Dreamplus Co. Ltd.) 400 mg daily in divided doses for 24 weeks increases hair count by 30% when compared with placebo. Self-rated improvement and satisfaction scores were 62% and 52% with pumpkin seed oil and placebo, respectively (92378). Clinical research in patients with female pattern hair loss shows that applying 1 mL of pumpkin seed oil to the scalp daily for 30 days improves hair regrowth similarly to minoxidil 5% foam, 1 mL daily (104974).
Interstitial cystitis. Although there is interest in using oral pumpkin for interstitial cystitis, there is insufficient reliable information about the clinical effects of pumpkin for this condition.
Intestinal parasite infection. Although there is interest in using oral pumpkin for intestinal parasite infection, there is insufficient reliable information about the clinical effects of pumpkin for this condition.
Overactive bladder. Oral pumpkin seed oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in females with overactive bladder shows that taking a specific combination product (Granu Fink femina, Omega Pharma) containing pumpkin seed oil 227 mg, sweet sumac bark extract 56 mg, and hops cone extract 18 mg three times daily for 12 weeks decreases the frequency of urination and leakage and improves quality of life when compared to baseline (103253). The validity of these findings is limited by the lack of a control group. Additionally, it is unclear if these findings are due to pumpkin seed oil, other ingredients, or the combination.
Urinary tract infections (UTIs). Although there is interest in using oral pumpkin for UTIs, there is insufficient reliable information about the clinical effects of pumpkin for this condition. More evidence is needed to rate pumpkin for these uses.

Selenium deficiency. Oral selenium is effective for the treatment and prevention of selenium deficiency. Details: Selenium supplementation is effective for reversing symptoms of selenium deficiency, as well as for preventing the development of selenium deficiency (4844,90357).

Autoimmune thyroiditis. Oral selenium seems to improve autoimmune thyroiditis in adults but not in children. Details: Clinical research in adults with thyroiditis shows that taking selenium up to 200 mcg daily in combination with levothyroxine reduces thyroid peroxidase antibodies by about 6% to 30% more than placebo after 3-12 months of treatment (9797,17510,17511,17512,17513,17515,17516,97943,104424). Selenium also seems to improve measures of quality of life such as feelings of well-being and mood (17515). Doses under 200 mcg daily might not be as effective (17512); selenomethionine might be more effective than sodium selenite (97943). Some research shows that selenium might be more effective in patients with more severe disease activity and less effective in patients with only moderate disease activity (9797,17513,17515). Also, selenium might not reduce thyroid autoantibodies in patients newly diagnosed with thyroiditis not receiving concurrent levothyroxine (97943). There is no reliable evidence about the effect of selenium on thyroid function or thyroid morphology. Despite positive findings in adults, clinical research in children suggests that taking selenium 50-200 mcg daily for 3-12 months does not significantly improve thyroid peroxidase antibodies, thyroglobulin antibody, or thyroid echogenicity (17514,90362).
Kashin-Beck disease. Selenium seems to help prevent Kashin-Beck disease, but does not improve symptoms in patients with existing disease. Details: A meta-analysis of prospective studies conducted in China shows that adding salt enriched with selenium to the diet of healthy children for up to 4 years reduces the odds of developing Kashin-Beck disease by 84% when compared with the use of iodine salt. Additionally, in children with Kashin-Beck disease, adding salt enriched with selenium to the diet might help heal metaphyseal lesions (97945). However, selenium does not seem to improve symptoms in those with existing disease. A clinical trial in children with Kashin-Beck disease shows that selenium supplementation does not improve joint pain or mobility when compared with placebo (55941).
Pre-eclampsia. Oral selenium might reduce the risk of pre-eclampsia in pregnant patients. Details: A meta-analysis of three low-quality clinical trials in pregnant patients shows that taking selenium 60-100 mcg daily for up to 6 months reduces the risk of pre-eclampsia by 72% when compared with placebo. Additionally, a meta-analysis of population research has found that the risk of pre-eclampsia is higher in pregnant patients with low selenium levels. Selenium levels were about 6.5 mcg/L lower in those who developed pre-eclampsia compared with those who did not (97946).

Asthma. Oral selenium does not seem to improve asthma symptoms. Details: Epidemiological research has found that plasma selenium concentration is not associated with asthma (74422). Also, clinical research in patients with asthma shows that taking selenium 100 mcg daily for 14-24 weeks does not improve symptoms, lung function, use of rescue inhalers, or quality of life when compared with placebo (74490,74387).
Atopic dermatitis (eczema). Oral selenium-enriched yeast does not seem to improve eczema symptoms. Details: A small clinical study in patients with eczema shows that taking selenium-enriched yeast 600 mcg daily for 12 weeks, either alone or in combination with vitamin E 600 IU daily, does not improve symptom severity when compared with placebo (74456).
Bladder cancer. Despite promising initial research, oral selenium does not seem to prevent bladder cancer development or recurrence. Details: In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and bladder cancer risk based on two small studies. However, the FDA determined that it is highly uncertain that selenium supplements reduce the risk of bladder cancer (102373). Since that time, the available research has not confirmed an association between selenium and bladder cancer risk. Epidemiological research has found that selenium supplementation is not associated with a reduced risk of bladder cancer (97085). Furthermore, a clinical study shows that taking selenium 200 mcg daily with or without vitamin E 400 IU daily for about 7 years does not prevent bladder cancer in older men (90352). Selenium also does not seem to prevent bladder cancer recurrence. A clinical study shows that taking selenium yeast 200 mcg daily for 3 years does not prevent the recurrence of bladder cancer when compared with placebo in patients that had undergone a transurethral resection for non-invasive bladder cancer (97087).
Cardiovascular disease (CVD). Most research shows that oral selenium does not reduce the risk of CVD. Details: Meta-analyses of clinical trials in patients with and without risk factors for CVD show that taking selenium alone or with other supplements for up to 8 years does not reduce the risk of CVD mortality or fatal and non-fatal CVD events (90360,97078). When reported, patients in these studies all had adequate plasma selenium levels at baseline (90360).
Colorectal cancer. Oral selenium does not seem to prevent cancer of the colon and rectum. Details: Epidemiological research has found no association between serum concentrations of selenium and the risk of developing colorectal cancer (74321,97085). Also, meta-analyses of clinical research, as well as individual clinical trials, show that taking selenium 100-200 mcg daily, alone or in combination with other vitamins and minerals, does not reduce the risk of colorectal cancer when compared with control (16707,34676,90361,97092).
Diabetes. Increased intake of selenium, either in the diet or as a supplement, is associated with an increased risk for developing type 2 diabetes. It is unclear if oral selenium is beneficial in patients with type 2 diabetes. Details: Observational research has found that high serum selenium levels, high dietary selenium intake, and selenium supplementation are each linked to an increased risk of developing diabetes (97091,99661). Consuming more than the recommended dietary allowance (RDA) of selenium daily is associated with an increased risk of developing diabetes when compared with consuming less than the RDA (99661). However, the effect of short-term selenium supplementation in patients with diabetes is unclear. Three small clinical trials in patients with type 2 diabetes and various other conditions, such as cardiovascular disease or kidney failure, show that taking selenium (Nature Made) 200 mcg daily for 8-24 weeks does not improve fasting blood glucose. However, taking selenium seems to reduce insulin resistance and improve insulin sensitivity and levels of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol when compared with placebo (97084,97086,109092). These three studies were included in a meta-analysis of 10 small, mostly moderate-quality clinical studies. This analysis shows that taking selenium 100-200 mcg daily for 4 to 24 weeks improves markers of insulin resistance and reduces serum insulin levels but does not lower fasting blood glucose when compared with placebo. Selenium supplementation did not reduce total or LDL cholesterol or triglycerides but may improve HDL cholesterol (110593). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the included studies, which enrolled patients with diabetes, gestational diabetes, cardiovascular disease, heart failure, or obesity. Additionally, all studies were conducted in Iran; it is unclear if these findings are generalizable to populations in other geographic locations.
Dyslipidemia. Most research shows that oral selenium supplementation does not improve cholesterol levels. Details: A meta-analysis of 11 clinical studies in adults with dyslipidemia shows that taking selenium 50-300 mcg daily for 8-24 weeks does not increase high-density lipoprotein (HDL) cholesterol levels or decrease total or low-density lipoprotein (LDL) cholesterol levels when compared with placebo. Taking selenium might modestly improve triglyceride levels, but this improvement is unlikely to be considered clinically significant (99662). Another meta-analysis of 21 mostly small, low-quality clinical studies, some of which were included in the prior meta-analysis, shows that taking various forms of selenium may modestly decrease total cholesterol levels, but does not improve triglycerides, LDL, or HDL cholesterol when compared with placebo (110595). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the included studies, which assessed various selenium dosing regimens and enrolled healthy patients or those with various cardiovascular and non-cardiovascular conditions.
Low birth weight. Oral or intravenous selenium supplementation does not improve outcomes in low birth weight infants. Details: Low selenium levels have been documented in low birth weight infants. However, selenium supplementation, orally or intravenously, does not appear to improve most outcomes in low birth weight infants. Clinical research shows that administering selenium, either as 7-10 mcg/kg daily parenterally or 5 mcg/kg daily orally, does not improve oxygen dependency or reduce the risk of death in low birth weight infants when compared with placebo. However, supplementation decreases the incidence of sepsis by up to 33% (74288,97083).
Lung cancer. Oral selenium does not reduce lung cancer risk in most patients. Details: A meta-analysis of three large clinical trials of over 20,000 patients, including patients with resected stage I non-small-cell lung cancer, shows that taking selenium 200-400 mcg daily for up to 5 years does not reduce the risk of lung cancer when compared with control (92912,97092). A secondary analysis of one of these studies found that selenium supplementation might reduce lung cancer risk in people with selenium levels below 105 ng/mL (9798). Also, a large study in healthy Chinese patients shows no benefit of using selenium in combination with other nutrients for over 5 years when compared with control (34539).
Nonmelanoma skin cancer. Oral selenium does not reduce the risk of nonmelanoma skin cancer and has been linked to increased risk in some patients. Details: Epidemiological research has found that higher selenium intake is not associated with a reduced risk of nonmelanoma skin cancer (97085). Furthermore, clinical research shows that taking selenium orally 200 mcg daily does not reduce the risk of basal cell carcinoma when compared with control (2664,10687). In addition, some evidence shows that daily selenium supplementation might increase the risk of squamous cell carcinoma and total non-melanoma skin cancer (10687).
Prostate cancer. Oral selenium does not seem to reduce prostate cancer risk. Details: Population studies have found that higher serum or toenail selenium levels are associated with a decreased risk of prostate cancer (8734,8735,8736,92911,10263). However, clinical research does not support this finding. A meta-analysis of 5 large clinical trials of over 20,000 patients shows that selenium 200-400 mcg daily for up to 5 years does not reduce the risk of prostate cancer when compared with control (97092). A 7-14 year follow-up study of one of these trials shows there was still no reduction of prostate cancer risk (17688). Selenium has also shown no benefit when used in combination with other supplements. In a large-scale clinical study (SU.VI.MAX), taking selenium 100 mcg in combination with vitamin C, vitamin E, beta-carotene, and zinc did not reduce prostate cancer risk (14135). In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and prostate cancer risk, stating that it is highly unlikely that selenium supplements reduce the risk of prostate cancer (102373).
Psoriasis. Oral selenium does not seem to reduce psoriasis severity. Details: Clinical research shows that taking selenium-enriched yeast 600 mcg daily for 12 weeks, either alone or in combination with vitamin E 600 IU daily, does not reduce the severity of psoriasis when compared with placebo (74460).
Sepsis. Intravenous selenium does not appear to improve outcomes in septic adults. Details: Earlier meta-analyses of clinical trials in septic adults showed that parenteral administration of selenium, along with routine nutritional interventions, reduces the risk of mortality by 11% to 27% when compared with placebo (90347,92907,92910). However, a more recent meta-analysis, which includes a large, multi-center study of over 1000 cases, shows that parenteral selenium does not reduce mortality in septic adults at 28, 90, or 180 days when compared with placebo (99658). Enteral selenium with other nutrients has been studied for sepsis in children. Clinical research in children shows that taking enteral selenium 40-400 mcg daily with zinc, glutamine, and IV metoclopramide is no more effective than whey protein for reducing time to first episode of nosocomial infection or sepsis in the intensive care unit (ICU). However, the selenium combination treatment might reduce the risk for sepsis in immunocompromised pediatric patients (86095).

Age-related cognitive decline. It is unclear if oral selenium reduces the risk of cognitive decline in older adults. Details: A cross-sectional study in elderly Americans has found that lower blood levels of selenium are associated with a greater risk of poor cognitive scores when compared with higher levels (104426).
Alcohol-related liver disease. Although there is interest in using oral selenium for alcohol-related liver disease, there is insufficient reliable information about the clinical effects of selenium for this condition.
Allergic rhinitis (hay fever). Although there is interest in using oral selenium for allergic rhinitis, there is insufficient reliable information about the clinical effects of selenium for this condition.
Arsenic poisoning. It is unclear if oral selenized yeast is beneficial for patients that were exposed to high levels of arsenic in the environment. Details: A small clinical study in Chinese people environmentally exposed to high concentrations of arsenic shows that taking selenized yeast providing 100-200 mcg of selenium daily for 14 months decreases the concentration of arsenic and symptoms of toxicity when compared with placebo (7831).
Benign prostatic hyperplasia (BPH). Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in men with BPH shows that taking selenium 240 mcg plus silymarin 570 mg daily for 6 months reduces lower urinary tract symptoms when compared with placebo (88155). Another clinical study in men with BPH shows that taking tamsulosin 0.4 mg plus a specific product containing selenium, saw palmetto, and lycopene (Profluss, Ayanda AS) daily for one year improves lower urinary tract symptoms and urodynamic parameters when compared with tamsulosin-alone (90354). It is unclear if these effects are due to selenium, other ingredients, or the combinations.
Burns. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies in patients with burns on 46% of their body surface suggest that taking a combination of copper 2.5-3.1 mg, selenium 315-380 mcg, and zinc 26.2-31.4 mg daily reduces the incidence of hospital-acquired pneumonia, but does not seem to improve wound healing, hospital stay, or mortality, when compared with placebo (6520,74382). Another very small clinical study in burn patients suggests that taking copper 4.5 mg, selenium 190 mcg, and zinc 40 mg daily reduces the duration of hospitalization, but does not have an effect on recovery and wound treatment requirements, when compared with standard dietary doses of these nutrients (74485).
Cancer. Selenium does not seem to reduce the risk of cancer in most people, but it might be beneficial in those with low selenium levels and in men. Details: Meta-analyses of clinical research and several clinical studies show that selenium supplementation does not reduce the incidence of cancer or cancer-related mortality when compared with control (14109,34538,74414,97078,97092). In clinical studies, selenium 100-400 mcg taken daily for 2-7.5 years with or without additional antioxidants did not reduce overall cancer risk (14109,34538,74414). However, most evidence did not assess baseline selenium levels. Other evidence suggests that selenium may have a benefit in men and in people with lower selenium levels. Epidemiological research has found that selenium intake at the recommended daily allowance (RDA) of 55 mcg or higher is associated with decreased cancer incidence and cancer mortality, especially in men (97085,103164). However, this research suggests that cancer risk was also influenced by age, body mass index, and smoking status (103164). Some clinical research also suggests that taking selenium might decrease the risk of cancer, when only men are considered (14109). An older meta-analysis of clinical research suggests that selenium was particularly beneficial in patients with lower baseline levels of selenium and in patients at high risk for cancer (90350). In 2003, the US Food and Drug Administration (FDA) approved a qualified health claim stating that consumption of selenium may produce anticarcinogenic effects and reduce the risk for certain forms of cancer. However, the FDA has determined that the evidence is limited and inconclusive (102374).
Cataracts. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An ancillary clinical study shows that taking selenium 200 mcg daily with or without vitamin E 400 IU daily for around 5.6 years does not reduce the risk of age-related cataracts in men when compared with placebo (92902).
Cervical dysplasia. It is unclear if oral selenized yeast is beneficial for patients with cervical dysplasia of mild severity. Details: A small clinical study in patients with cervical intraepithelial neoplasia grade 1 (CIN1) shows that taking yeast containing selenium 200 mcg daily for 6 months resulted in regression of CIN1 in 88% of participants, compared with regression in only 55% of participants taking placebo (97944).
Chemotherapy-induced nephrotoxicity. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in cancer patients shows that drinking a beverage containing vitamin C, vitamin E, and selenium does not prevent cisplatin-induced nephrotoxicity when compared with a placebo beverage (74340). However, poor compliance to treatment may limit the validity of these findings.
Chronic fatigue syndrome (CFS). Although there is interest in using oral selenium for CFS, there is insufficient reliable information about the clinical effects of selenium for this condition.
Cirrhosis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with primary biliary cirrhosis shows that taking a combination of selenium, vitamin A, vitamin C, vitamin E, methionine, and coenzyme Q10 for 12 weeks does not improve fatigue or any other disease-related symptoms when compared with placebo (34494).
Cisplatin-associated ototoxicity. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in cancer patients shows that drinking a beverage containing vitamin C, vitamin E, and selenium does not prevent cisplatin-associated hearing loss when compared with placebo beverage (74340). However, poor compliance to treatment may limit the validity of these findings.
Colorectal adenoma. It is unclear if oral selenium prevents recurrence of adenomas in the colon and rectum. Details: A large clinical study in patients with a history of colorectal adenomas shows that taking a specific selenium supplement (SelenoExcell High Selenium Yeast, Cypress Systems) 200 mcg daily for about 33 months does not reduce adenoma recurrence when compared with placebo. However, in a sub-group of patients with advanced adenomas at baseline, selenium seems to reduce risk of recurrence by 18% when compared with placebo (97091). Some research also shows that taking selenium in combination with zinc, and vitamins A, C, and E reduces adenoma recurrence when compared with placebo (92903). It is not clear any benefit is due to selenium, other nutrients, or the combination.
Congestive heart failure (CHF). Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study in elderly patients with heart failure living in Sweden shows that taking a specific selenium supplement (SelenoPrecise, Pharma Nord) 200 mcg plus a specific coenzyme Q10 supplement (Bio-Quinon, Pharma Nord) 200 mg daily for about 4 years reduces the risk of cardiovascular mortality by about 55% when compared with placebo (92904). The risk reduction seems to be most pronounced in patients with lower selenium levels (97906). Furthermore, at 10- and 12-year follow-ups, cardiovascular mortality in the treatment group continued to be 49% and 41% lower, respectively, when compared with placebo (96546,97466). It is unclear if the benefit can be attributed to selenium, coenzyme Q10, or the combination.
Coronary artery bypass graft (CABG) surgery. It is unclear if oral selenized yeast is beneficial for patients undergoing CABG surgery. Details: A small clinical study in patients undergoing CABG surgery shows that taking selenium 200 mcg daily as selenium yeast for 4 weeks improves glycemic control, lipid levels, and markers of inflammation when compared with placebo (103163). It is not known whether this influences the outcome or complications of CABG surgery.
Critical illness (trauma). Evidence on the use of intravenous selenium in critically ill patients is conflicting. Details: The most recent meta-analysis of 24 clinical trials in critically ill patients shows that intravenous selenium does not improve survival over 6 months, shorten hospital stay, or reduce intensive care unit (ICU) stay, infectious complications, development of acute kidney failure, or duration of mechanical ventilation when compared with control. Also, length of ICU stay was increased by about 4.5-fold in patients receiving selenium in doses of more than 1000 mcg daily (109086). These findings are similar to those of a meta-analysis of 21 randomized controlled trials in critically ill patients from 2016 which shows that intravenous selenium given alone or with other nutrients does not improve mortality, duration of hospital stay, or kidney function when compared with control (97090). However, another recent meta-analysis of 19 clinical trials in critically ill patients shows that intravenous selenium reduces total mortality by 14% and shortens hospital stay by about 2 days when compared with control, without affecting ICU stay, duration of mechanical ventilation, or mortality over 28 days (101345). The reasons for these discrepancies are not clear and do not seem to be completely explained by differences in doses or durations of selenium (109086). Some reasons for the discrepancies might include differing analytic methods used in meta-analyses, as well as variations in forms of selenium, concomitant treatments, and specific patient populations. One sub-analysis shows that, when limited to randomized controlled trials examining the effect of selenium supplementation in patients sustaining traumatic injury, the odds of mortality was reduced by about 26% and duration of ICU and hospital stay were modestly reduced. There was no effect on infectious complications (109090).
Dementia. It is unclear if oral selenium prevents dementia or reduces symptoms. Details: Observational research has found that taking selenium 200 mcg daily for 4 years does not decrease the incidence of dementia in men 60 years or older (93570). However, the follow-up period may not have been long enough to reliably detect the effect of selenium on the development of dementia. Also, the screening method used to detect new cases of dementia may have failed to identify individuals presenting with only the initial symptomatic stages of the disease (93570,93571).
Depression. It is unclear if oral selenium is beneficial for the treatment of prevention of depression. Details: A meta-analysis of observational research has found no difference in serum levels of selenium between patients with or without depression. In addition, serum levels of selenium do not correlate with depression scores (109091). A meta-analysis of clinical research shows that selenium supplementation, usually 100-200 mcg daily, modestly reduces symptoms of depression; however, at least one of the three studies included in this meta-analysis investigated the effects of selenium in patients with postpartum depression, specifically (109091). These meta-analyses are limited by the quality of included research and the small number of available studies.
Diabetic nephropathy. It is unclear if oral selenium alleviates diabetic nephropathy symptoms. Details: A small clinical study in patients with diabetic nephropathy shows that taking selenium (Nature Made) 200 mcg daily for 12 weeks does not improve kidney markers such as blood urea nitrogen or serum creatinine when compared with placebo (97084).
Dilated cardiomyopathy. There is limited evidence on the oral use of selenium in patients with Keshan disease and peripartum cardiomyopathy. Details: Observational research in patients with a specific type of dilated cardiomyopathy called Keshan disease and congestive heart failure has found that selenium supplementation is associated with a 61% decreased risk of cardiac death when compared with no supplementation (101346). A small clinical study in patients with peripartum cardiomyopathy and selenium deficiency shows that taking selenium 200 mcg daily for 3 months does not seem to improve heart failure symptoms or left ventricle systolic function, or prevent death, when compared with no treatment (104420).
Esophageal cancer. Limited research suggests that oral selenium does not reduce esophageal cancer risk. Details: Low quality clinical research suggests that taking selenium supplements alone or with other vitamins does not decrease the risk of esophageal cancer when compared with control (4679,12185).
Gastric cancer. Oral selenium has only been evaluated in combination with other ingredients and in a specific patient population; its effect when used alone and in other populations is unclear. Details: Population research in Chinese patients has found that high levels of selenium are associated with lower risk of gastric cancer and cancer mortality (97948). However, clinical research does not agree. A large clinical study in patients residing in China shows that taking selenium 37.5 mcg in combination with vitamin C 250 mg and vitamin E 100 IU twice daily for about 7.3 years does not reduce the risk of developing gastric cancer or precancerous gastric lesions when compared with placebo. This combination treatment was not associated with reduced gastric cancer incidence or mortality at the 14-year follow-up of this study (14447,51470). Another clinical study in healthy Chinese adults also shows that taking a combination of selenium 50 mcg, vitamin E 30 mg, and beta-carotene 15 mg daily for 5.2 years does not reduce the risk of gastric cancer when compared with control (4679). It is unclear if these findings are generalizable to populations in geographic locations other than China.
Graves' ophthalmopathy. It is unclear if oral selenium is beneficial for Graves' ophthalmopathy. Details: A small clinical trial in adults with Graves' ophthalmopathy shows that taking selenium 100 mcg twice daily for 6 months is modestly beneficial for reducing disease activity, based on signs and symptoms including pain, swelling, and redness, when compared with placebo (109085).
Hepatitis C. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with hepatitis C shows that taking a combination of selenium 200 mcg, vitamin C 500 mcg, and vitamin E 945 IU daily for 6 months does not have an effect on levels of alanine aminotransferase or viral load when compared with placebo (74377).
HIV/AIDS. It is unclear if oral selenium improves outcomes in patients with HIV. Details: Clinical trials in HIV-positive men and women, most receiving anti-retroviral therapy (ART), shows that taking selenium 200 mcg daily for up to 2 years can reduce HIV-1 viral load, increase CD4 cell counts, and lower the risk of hospitalizations when compared with placebo (15266,74314). However, not all research agrees. Two small clinical trials in HIV-positive patients taking ART shows that taking selenium 100-200 mcg daily for 6-12 months does not reduce the risk for opportunistic infections and does not increase CD4 counts when compared with control (7830,104417). Furthermore, selenium does not seem to benefit patients that are not receiving conventional ART. A large clinical study in HIV-infected pregnant patients in Tanzania with poor access to ART shows that taking selenium 200 mcg daily with prenatal vitamins until 6 months after delivery, does not improve progression of HIV nor pregnancy outcomes when compared with no selenium supplementation (74419). Another large clinical study in HIV-infected and ART-naïve patients in Botswana shows that taking selenium 200 mcg daily for 24 months does not slow HIV progression when compared with placebo (92905).
Hypertension. It is unclear if oral selenium improves blood pressure. Some evidence suggests selenium supplementation may slightly increase systolic blood pressure. Details: A meta-analysis of 5 small clinical studies in adults with various health conditions shows that taking selenium or selenium yeast 100-200 mcg/day for 6-12 weeks may increase systolic blood pressure by about 2 mmHg but does not impact diastolic blood pressure when compared with placebo (110595). However, the validity of the findings from this meta-analysis is limited by the heterogeneity of the included studies, which enrolled patients with preeclampsia, gestational diabetes, obesity, or heart failure. Additionally, all studies were conducted in Iran; it is unclear if these findings are generalizable to populations in other geographic locations.
Hyperthyroidism. It is unclear if oral selenium alleviates symptoms in patients with Graves' disease. Details: A small clinical study in patients with Graves' hyperthyroidism shows that taking sodium selenite 300 mcg daily in addition to treatment with methimazole for 24 weeks does not affect symptoms or recurrence rates when compared with placebo plus methimazole (97089). Oral selenium has also been studied in combination with other supplements. A small preliminary clinical trial in patients with newly diagnosed Graves' disease and low levels of selenium and vitamin D shows that taking selenium 100 mcg daily for 180 days along with vitamin D as cholecalciferol 7000 IU weekly for 270 days, in addition to methimazole, modestly reduces levels of serum free thyroxine and improves quality of life when compared with methimazole alone. However, taking selenium and vitamin D did not affect levels of free triiodothyronine or positive thyroid stimulating hormone (TSH) receptor antibody (109049).
Hypothyroidism. It is unclear if oral selenium improves thyroid hormone balance in elderly individuals, pregnant patients, or patients with subclinical hypothyroidism. In patients with iodine deficiency, selenium supplementation may be harmful. Details: Low selenium levels or selenium deficiency seems to reduce conversion of thyroxine (T4) to triiodothyronine (T3). However, clinical research in healthy elderly patients is conflicting. Although one study shows that taking selenium 100 mcg daily for 3 months increases conversion of T4 to T3 when compared with placebo (17508), a larger study shows that taking selenium 100-300 mcg daily for 6 months does not impact conversion of T4 to T3 when compared with placebo (17509). Additionally, taking selenium can worsen hypothyroidism in people with iodine deficiency. People who are iodine- and selenium-deficient should not receive selenium supplements without concomitant iodine. In these individuals, selenium increases conversion of T4 to T3, but the thyroid gland lacks iodine to synthesize more T4 (1664,14563,14564,14565,17508). Selenium does not have a significant effect on thyroid function when iodine intake is adequate (1664,4844). In pregnant patients with hypothyroidism, clinical research shows that taking selenium does not reduce complications such as pre-eclampsia or preterm birth. However, selenium might improve postpartum thyroid function and decrease the risk of postpartum thyroiditis (17507). Also, taking selenium 200 mcg daily during pregnancy seems to reduce the risk of developing postpartum thyroid dysfunction and permanent hypothyroidism by 41% and 42%, respectively, when compared with placebo in euthyroid pregnant patients who are positive for thyroid peroxidase antibodies (74391). Selenium supplementation has also been studied for subclinical hypothyroidism. Clinical research in females aged 18 to 50 years with or at risk for subclinical hypothyroidism in Slovakia shows that taking selenium 83 mcg daily and myo-inositol 600 mg daily for 6 months modestly reduces thyroid stimulating hormone (TSH) and thyroid auto-antibody titers when compared with baseline. Selenium and myo-inositol supplementation also reduced patient-reported hypothyroid symptoms including fatigue, menstrual cycle irregularity, and intolerance to heat or cold (110591). The interpretation of these results is limited by the lack of a control group. In addition, it is unclear if these effects are due to selenium, myo-inositol, or the combination.
Influenza. Although there is interest in using oral selenium for influenza, there is insufficient reliable information about the clinical effects of selenium for this condition.
Kidney failure. It is unclear if oral selenium is beneficial for improving lipid parameters in patients on hemodialysis. Details: Selenium levels may be low in patients undergoing chronic hemodialysis, and supplementation might be needed (1805,11053). However, clinical research in patients on hemodialysis shows that taking selenium daily for 3 months does not improve the lipid profile when compared with taking placebo (109095).
Lichen planus. It is unclear if topical or oral selenium alleviates oral lichen planus symptoms. Details: A small clinical study in patients with oral lichen planus shows that applying a selenium hydrogel (selenomethionine 14 mcg/gram) twice daily for 6 weeks seems to significantly reduce pain at a 12 week follow-up, but not immediately after use, when compared with applying topical corticosteroids and antifungal agents 2-4 times daily. Taking oral selenium 200 mcg twice daily for 6 weeks seems to be no different than the topical corticosteroids and antifungal treatment at both time points (104422).
Liver cancer. It is unclear if oral selenium reduces liver cancer risk. Details: Preliminary clinical research in China suggest that taking selenium 200 mcg daily for 2-5 years can reduce the incidence of liver cancer when compared with control (74389). The benefit of selenium on prevention of liver cancer in Western countries is unknown.
Lymphedema. It is unclear if oral selenium reduces lymphedema complications. Details: Preliminary clinical research in patients with secondary lymphedema after breast cancer surgery shows that taking a sodium selenite solution 1000 mcg daily for 1 week followed by 300 mcg daily for 2 weeks and then 200 mcg daily for a total of 15 weeks might reduce recurrence of erysipelas, a type of bacterial skin infection, when compared with placebo (15334).
Male infertility. It is unclear if oral selenium, used alone or in combination with other antioxidants, improves pregnancy or live birth rates for couples with idiopathic male infertility. Details: Meta-analyses of 2-3 clinical trials show that taking selenium, alone or in combination with other antioxidants, for 12-26 weeks modestly improves sperm count and motility when compared with placebo. However, pregnancy rates and live birth rates were only studied in one clinical trial each, with no statistical evidence of benefit (109094). Studies included in the analysis used selenium 26-200 mcg daily for 12-26 weeks, either alone or in combination with vitamin A 1 mg, vitamin C 10 mg, and vitamin E 15 mg; vitamin E 400 IU and folic acid 5 mg; lycopene 6 mg, vitamin E 400 IU, vitamin C 100 mg, zinc 25 mg, folate 0.5 mg, and garlic 1000 mg; or N-acetyl-cysteine 600 mg (74526,74493,102968,109094).
Mercury toxicity. It is unclear if oral selenium improves clearance of mercury and reduces symptoms of toxicity. Details: A small clinical trial in Chinese adults environmentally exposed to high concentrations of mercury shows that taking selenium-enriched yeast, containing selenium 100 mcg, daily for 3 months increases urinary excretion of mercury when compared with control (90351).
Muscular dystrophy. There is limited evidence on the oral use of selenium in Duchenne muscular dystrophy. Details: Preliminary clinical research suggests that supplementation with sodium selenite 1 mg daily for 6 months does not improve disease activity in patients with muscular dystrophy (74455).
Obesity. It is unclear if oral selenium is beneficial for weight reduction. Details: A small clinical study in adults with obesity shows that taking selenium 240 mcg daily and following a low-calorie diet for 3 months is no different for weight reduction when compared with following a low-calorie diet alone (104416).
Oral mucositis. It is unclear if oral selenium is beneficial for reducing oral mucositis in patients undergoing radiotherapy. Details: A small clinical study in patients with head and neck cancers shows that taking selenium 200 mcg twice daily for the duration of radiation therapy does not seem to reduce the incidence or severity of oral mucositis when compared with placebo (104421). It is unclear if other doses or routes of administration might be beneficial.
Osteoarthritis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with osteoarthritis shows that taking a specific selenium-containing combination supplement (Selenium-ACE) does not improve most clinical symptoms when compared with placebo (74449).
Ovarian cancer. It is unclear if oral selenium reduces ovarian cancer risk. Details: Epidemiological research has found that there is no association between dietary selenium intake and the risk of developing ovarian cancer (74342).
Overall mortality. Although oral selenium does not seem to reduce overall mortality risk in most patients, it might have benefit in patients with low nutrient intake. Details: Meta-analyses of clinical research show that selenium supplementation, alone or in combination with other micronutrients, does not reduce all-cause mortality when compared with placebo (15305,90360,97078). Selenium might also not be beneficial when used in combination with non-nutrient supplements. An additional large clinical study in elderly patients in Sweden shows that taking selenium 200 mcg daily plus coenzyme Q10 100 mg twice daily for around 5 years does not reduce the risk of all-cause mortality when compared with placebo. The baseline selenium status of these patients is unclear (92904). Despite these results, some evidence suggests that selenium used with other nutrients might have benefit in patients with low nutrient intake. In a large clinical study, selenium in combination with zinc, vitamin C, vitamin E, and beta-carotene lowered all-cause mortality risk in men, but not women, when compared with control (14109). Researchers speculate that this result occurred because men have a lower intake of dietary antioxidants than women. Another large clinical study in Chinese patients with chronically low nutrient intake shows that taking selenium with beta-carotene and vitamin E decreases stroke mortality, cancer mortality, and total mortality when compared with control (2673).
Pancreatic cancer. It is unclear if oral selenium reduces pancreatic cancer risk. Details: Some epidemiological research has found that increased selenium intake is associated with a 34% lower risk of pancreatic cancer (97093). However, other observational research has found no association (101342).
Pancreatitis. Although there is interest in using oral selenium for pancreatitis, there is insufficient reliable information about the clinical effects of selenium for this condition.
Polycystic ovary syndrome (PCOS). It is unclear if oral selenium is beneficial for PCOS. Details: A small clinical study in patients with PCOS shows that taking selenium (Nature Made) 200 mcg daily for 8 weeks results in a significantly higher pregnancy rate of 19%, compared with 3% in those taking placebo. The incidences of alopecia and acne were reduced by 77% and 73%, respectively. There were also modest reductions in hirsutism severity and serum levels of high sensitivity C-reactive protein (hs-CRP) and dehydroepiandrosterone (DHEA); however, there was no effect on other hormone levels (109096). Another small clinical study in patients with PCOS undergoing in vitro fertilization shows that taking selenium yeast 200 mcg daily for 8 weeks improves measures of insulin sensitivity and reduces serum insulin and fasting blood glucose levels when compared with placebo. However, selenium supplementation does not improve the pregnancy rate or lipid parameters (110596). The effect of selenium supplementation on the live birth rate in this population is unclear. Selenium has also been studied in combination with other supplements for patients with PCOS. A small clinical study in adults with PCOS shows that taking selenium 200 mcg daily for 12 weeks, in conjunction with a combination probiotic product, modestly improves subjective scores of depression, anxiety, and stress when compared with placebo. Taking this combination also modestly reduces total testosterone levels and subjective ratings of hirsutism when compared with placebo (99659). It is not clear if these effects are due to selenium, the probiotic, or the combination.
Postpartum depression. It is unclear if oral selenium is beneficial for postpartum depression. Details: A meta-analysis of two observational studies has found that a high selenium intake is associated with a modestly reduced risk of postpartum depression. The effect of selenium supplementation on symptoms of postpartum depression is unclear. One moderate-sized clinical trial included in this publication shows that taking selenium reduces symptoms of postpartum depression (109091).
Pregnancy-induced hypertension. It is unclear if oral selenium reduces the development of hypertension during pregnancy. Details: A small clinical study in pregnant patients shows that drinking a dietary liquid containing selenium 100 mcg daily for 6-8 weeks seems to decrease the incidence of pregnancy-induced hypertension when compared with placebo (74481).
Premature rupture of membranes (PROM). It is unclear if oral selenium during pregnancy prevents PROM. Details: One clinical trial shows that taking selenium 100 mcg daily from the first trimester of pregnancy until delivery significantly reduces the incidence of PROM to 13%, compared to 34% with placebo (109097).
Radiation-induced diarrhea. It is unclear if oral selenium reduces diarrhea in patients receiving radiation therapy for cancer. Details: A small clinical study in patients with cervical or endometrial cancer shows that taking selenium 500 mcg on days of radiation therapy and 300 mcg on days without radiation therapy reduces the incidence of radiation-induced diarrhea to 20.5%, compared to 44.5% in the control group not taking selenium. This benefit appears to be more pronounced in patients receiving a larger (>1302 mL) planning target volume of radiation (90355).
Rheumatoid arthritis (RA). It is unclear if oral selenium, as selenized yeast, reduces RA symptoms. Details: A small clinical study in patients with RA suggests that taking selenized yeast, providing selenium 200 mcg, daily for 90 days does not improve objective measures of RA when compared with placebo. However, there might be small improvements in quality of life measures (9763).
Schizophrenia. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with schizophrenia shows that taking a combination of selenium (Nature Made) 200 mcg and a combination probiotic mixture (LactoCare, Zisttakhmir Company) daily for 12 weeks modestly improves general positive and negative symptoms of schizophrenia, but not positive or negative scores, when compared with placebo. There were also modest improvements in levels of high-sensitivity C-reactive protein (CRP), fasting glucose, insulin resistance, and insulin sensitivity, but not lipid parameters (109087).
Statin-induced myopathy. Small clinical studies suggest that oral selenium may not improve symptoms of myopathy in patients taking statins. Details: Small clinical studies in patients with statin-induced myopathy suggests that taking selenium (SelenoPrecise, Pharma Nord) 200 mcg daily with or without coenzyme Q10 for 3 months does not improve myopathy symptoms when compared with placebo (92908,92909).
Stroke. It is unclear if intravenous selenium improves neurological outcomes following a stroke. Details: A small clinical trial in patients with a recent first ischemic stroke shows that intravenous sodium selenite pentahydrate (Selenase, Biosyn, Arzenitmittel GmbH) 2000 mcg after admission and then 1000 mcg daily for 5 days modestly improves some, but not all, measures of neurological deficits when compared with placebo (109088). Another small clinical trial in patients with a recent ischemic stroke shows that the same intervention improves some neurological outcome measures on day 7 or at an earlier discharge, but benefits were not maintained at 3 months (109093). The effects of oral selenium on neurological outcomes following a stroke have not been investigated.
Succinylcholine-induced myalgia. It is unclear if oral selenium is beneficial for preventing succinylcholine-induced postoperative myalgia. Details: Clinical research in patients receiving succinylcholine for a sinuscopy shows that taking a single dose of selenium 200 mcg 2 hours before anesthesia induction modestly decreases the incidence of postoperative myalgia at 24 hours. In those taking selenium, 95% of patients had no postoperative myalgia, compared with 77.5% of those taking placebo. Postoperative analgesia requirements were also modestly reduced; however, there was no difference in overall pain or the incidence of muscle twitching (109089).
Thyroid cancer. It is unclear if oral selenium reduces the risk of thyroid cancer in most patients. Details: In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding selenium and thyroid cancer risk. This qualified health claim was based on one weak and limited study. The FDA has determined that it is highly uncertain that selenium supplements reduce the risk of thyroid cancer (102373). More recent observational research in postmenopausal individuals using data from the Women's Health Initiative has found that selenium intake at or above the recommended daily allowance from dietary sources or supplements is not associated with a decreased risk of thyroid cancer (110590).
Ulcerative colitis. Oral selenium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in patients with ulcerative colitis shows that taking a liquid supplement containing a combination of selenium, fish oil, fructo-oligosaccharides, acacia, vitamin E, and vitamin C daily for 6 months does not improve disease activity scores when compared with placebo. However, taking the combination supplement seems to reduce the need for oral prednisone for symptom control (13757). The effect of selenium alone is unclear. More evidence is needed to rate selenium for these uses.

Cognitive function. It is unclear if consuming spinach is beneficial for cognitive function. Details: Preliminary clinical research in healthy adults shows that consuming spinach 200 grams with lunch does not improve attention or memory after 150 minutes when compared with a rice milk control (96852).
Muscle strength. It is unclear if oral spinach is beneficial for muscle strength. Details: A small, preliminary clinical study in healthy adults over 50 years of age shows that taking an aqueous spinach extract, 1 gram orally twice daily, in conjunction with a moderate-intensity exercise program, 3 sessions per week of 1 hour each for 12 weeks, improves several measures of muscle strength and quality in both sexes, and increases lower leg muscle mass in males, when compared with placebo (109546).
Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral spinach can reduce the risk of developing NAFLD. Details: A large observational study has found that raw, but not boiled, spinach consumption is inversely associated with the risk of developing NAFLD (106566).
Obesity. It is unclear if consuming spinach is beneficial for weight loss. Details: Preliminary clinical research in overweight or obese middle-aged and older females shows that taking a specific spinach product (Appethyl, Greenleaf Medical AB) 5 grams daily before breakfast for 12 weeks increases weight loss by an additional 1.5 kg when compared with placebo. However, fat loss, waist circumference, and blood lipids are not improved when compared with placebo (96856,96857).
Polycystic ovary syndrome (PCOS). It is unclear if oral spinach-derived thylakoids are beneficial for PCOS. Details: A small clinical study in premenopausal adults with PCOS and obesity shows that adding 5 grams orally daily of spinach-derived thylakoids to a low-calorie diet for 12 weeks reduces weight and body mass index (BMI) by 8%, compared with 4% with placebo and the low-calorie diet. Insulin resistance is also improved among those receiving spinach extract. These changes are unlikely to be clinically significant (106568). More evidence is needed to rate spinach for these uses.

Bladder cancer. Consuming tomatoes and tomato-based products does not appear to reduce the risk of bladder cancer. Details: Observational studies have found no association between tomato and tomato-based product intake and the risk of bladder cancer (2407).
Breast cancer. Consuming tomatoes and tomato-based products does not appear to reduce the risk of breast cancer. Details: Observational studies have found no association between tomato or tomato-based product intake and risk of breast cancer (15747).
Diabetes. Consuming tomatoes and tomato-based products does not appear to prevent the development of type 2 diabetes or improve glycemic control in patients with type 2 diabetes. Details: Observational studies have found that increasing intake of tomato or tomato-based products does not significantly decrease the risk of developing type 2 diabetes (14004,14361). Additionally, a small clinical study in non-smoking male patients with type 2 diabetes shows that consuming raw tomato 200 grams daily for 8 weeks does not improve plasma glucose levels when compared to baseline (102477). The validity of this finding is limited by the lack of comparator group.

Aging skin. It is unclear if tomato improves skin appearance. Details: A small study of females aged 35-55 shows that taking a certain tomato pulp product (Lumenato, Lycored) 1 capsule daily for 12 weeks improves patient reported skin appearance scores when compared to baseline (110523). The interpretation of this result is limited by the lack of a placebo group.
Benign prostatic hyperplasia (BPH). Oral tomato powder has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with BPH shows that taking 5 grams of a whole tomato food supplement consisting of tomato powder and polyphenols extracted from olives daily for 2 months improves quality of life and reduces lower urinary tract symptoms including urinary frequency, urinary urgency, and nocturia when compared to baseline. No improvements in these symptoms were reported with placebo (106656). It is unclear if these findings are due to tomato, olive polyphenols, or the combination.
Cardiovascular disease (CVD). It is unclear if consuming tomato-based foods reduces the risk of cardiovascular events. Details: Observational research has found that increased consumption of tomato-based foods is associated with an insignificant trend towards a reduced risk of myocardial infarction, stroke, and other cardiovascular events (10418,102178).
Cataracts. It is unclear if consuming tomatoes reduces the risk of cataracts. Details: Observational research has found that eating more than 3 servings of tomatoes each week may decrease the risk of developing cataracts (9439).
Cervical cancer. It is unclear if consuming tomatoes reduces the risk of cervical cancer. Details: Observational research has found that increased tomato intake is associated with a decreased risk of cervical cancer (2407).
Colorectal cancer. Research on the benefits of consuming tomatoes or tomato-based products for the prevention of colorectal cancer is conflicting and limited to observational studies only. Details: Some observational research has found that increasing tomato or tomato-based product intake is associated with a reduced risk of colorectal cancer (2404,2407). However, higher quality observational research has found that tomato-based product intake is not associated with risk of colorectal cancer (15747).
Exercise-induced asthma. It is unclear if oral tomato extract is beneficial in patients with exercise-induced asthma. Details: A small clinical study in patients with exercise-induced asthma shows that taking a specific tomato extract (Lyc-O-Mato, LycoRed Ltd) 30 mg daily for 1 week seems to reduce exercise-induced asthma when compared with placebo. The tomato extract seems to prevent decreases in forced expiratory volume (FEV1) in response to exercise (7898).
Gastric cancer. Research on the benefits of consuming tomatoes or tomato-based products for the prevention of gastric cancer is conflicting and limited to observational studies only. Details: Some observational studies have found that increasing tomato or tomato-based product intake is associated with a reduced risk of gastric cancer in some subgroups of patients (2407,15747,102480). However, other observational research has found that tomato-based product intake is not associated with risk of gastric cancer (15747). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding tomatoes and gastric cancer risk. However, the FDA concludes that it is highly unlikely that tomatoes reduce the risk of gastric cancer (102375).
Hyperlipidemia. Small clinical studies suggest that consuming tomato sauce or semi-dried tomatoes may modestly reduce low-density lipoprotein (LDL) cholesterol levels in patients with hyperlipidemia. Details: One small, open-label clinical trial in patients with hyperlipidemia shows that consuming a specific vine-ripened tomato sauce (OsteoCol, C.G. Food, SRL) 150 mL daily for 6 weeks reduces total cholesterol and LDL cholesterol levels when compared to baseline. Patients adherent to the tomato sauce regimen showed an 11 mg/dL and 12 mg/dL reduction in total and LDL cholesterol, respectively, while those consuming a sterol-enriched yogurt saw total and LDL cholesterol levels decrease by 18 mg/dL and 16 mg/dL, respectively. Patients with a baseline LDL cholesterol level of greater than 152 mg/dL saw the greatest benefit from this tomato sauce (106653). Another small clinical study in Japanese patients with borderline high cholesterol shows that taking 50 grams of a semi-dried tomato containing lycopene 22-27.8 mg daily for 12 weeks modestly reduces LDL cholesterol levels but does not affect high-density lipoprotein (HDL) cholesterol levels when compared with taking 50 grams of a tomato without lycopene (102180). This suggests that any benefit of tomato on blood lipid levels is likely due to its lycopene content.
Hypertension. Small clinical studies suggest that oral tomato extract may modestly reduce blood pressure in patients with hypertension. Details: Several small clinical trials in patients with hypertension show that taking a specific tomato extract product (Lyc-O-Mato, LycoRed, Ltd.), providing lycopene 15-30 mg daily, for 6-8 weeks, reduces systolic blood pressure by around 7-13 mmHg and diastolic blood pressure by around 4-6 mmHg when compared to baseline (14287,60415,102182). The validity of these findings is limited by the lack of a comparator group. Evidence on the use of tomato in patients with pre-hypertension is mixed. One small clinical study in patients with pre-hypertension shows that taking a specific tomato extract (Fruitflow, Provexis Plc, UK.) 150 mg as a single dose seems to modestly reduce blood pressure over a 24-hour period when compared with placebo (102478). This study is limited by its small size and short duration. Another small clinical study in pre-hypertensive patients shows that taking a specific tomato extract (Lyc-o-Mato, LycoRed Ltd) containing lycopene 15 mg daily for 8 weeks does not reduce blood pressure when compared with placebo (42079). The impact of dietary tomato consumption on preventing hypertension has also been evaluated. A large prospective observational study in Chinese adults without a history of smoking or myocardial infarction suggests moderate dietary intake of tomatoes (i.e. up to 33.3 grams daily) is associated with a 49-58% reduction in the risk of developing new onset hypertension when compared with no consumption after about 6 years' follow up. However, the associated risk reduction was less with higher consumption (110525). These results may not apply to patients in countries where dietary trends are different, and the validity of these findings is limited by the potential for confounding.
Lung cancer. It is unclear if consuming tomatoes reduces the risk of lung cancer; the available research is conflicting. Details: Some observational studies have found an association between increased tomato and tomato-based product consumption and a reduced risk of lung cancer; however, many of these studies were not stratified based on the patient's smoking status. Higher quality, large-scale observational studies have not found any association between tomato product intake and lung cancer risk (15747).
Muscle strength. It is unclear if consuming tomatoes improves muscle strength or attenuates declines in muscle strength. Details: A small observational study in Japanese adults 22-68 years of age found that more frequent tomato consumption (2 or more times weekly) is associated with an attenuated rate of handgrip strength decline over 3 years when compared with less frequent tomato consumption (102473).
Ovarian cancer. Research on the benefits of consuming tomatoes or tomato-based products for the prevention of ovarian cancer is conflicting and limited to observational studies only. Details: Some observational research has found that increased tomato or tomato juice intake is not associated with risk of ovarian cancer; however, consuming tomato sauce two or more times weekly is associated with a decreased risk (2407). Other observational research has found that increased dietary intake of lycopene, particularly from tomato sauce, is associated with a reduced risk of ovarian cancer in premenopausal patients (10133). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding tomato sauce and ovarian cancer risk. However, the FDA concludes that it is highly uncertain that tomato sauce reduces the risk of ovarian cancer (102375).
Pancreatic cancer. Research on the benefits of consuming tomatoes or tomato-based products for the prevention of pancreatic cancer is conflicting and limited to observational studies only. Details: A large-scale observational study have found that that tomato or tomato-based product intake is not associated with a decreased risk of pancreatic cancer (15747). However, other observational studies have found that raw tomato intake, and high tomato intake in general, is associated with a reduced risk of pancreatic cancer (2407,15747,15750). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding tomatoes and pancreatic cancer risk. However, the FDA concludes that it is highly unlikely that tomatoes reduce the risk of pancreatic cancer (102375).
Prostate cancer. Consuming tomatoes or tomato-based products may slightly lower the risk of prostate cancer; however, observational research is mixed and high-quality clinical trials addressing tomato intake and prostate cancer risk are lacking. Details: Some observational studies have found that consuming tomato products, including tomatoes, tomato sauce, pizza, or tomato juice, one time or more per week, is associated with a modest reduction in the risk of prostate cancer (2406,7772,7895,12878,15747,102476). However, other observational research has found that tomato consumption is not associated with a reduced risk of prostate cancer (14125,15172,15747,92171). One small clinical study in patients with high-grade prostatic intraepithelial neoplasia shows that taking tomato extract capsules containing lycopene 30 mg daily for 6 months does not impact benign tissue endpoints when compared with placebo (102471). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim stating that one-half to one cup of tomatoes or tomato sauce weekly may reduce the risk of prostate cancer. However, the FDA concludes that there is little scientific evidence to support this claim (102375).
Radiation dermatitis. It is unclear if drinking tomato juice is beneficial in patients with radiation dermatitis. Details: One small, uncontrolled clinical trial in patients undergoing radiotherapy for breast cancer shows that drinking tomato juice 160 mg daily for 6 months after radiotherapy improves the severity of dermatitis within 1 month of treatment when compared to baseline (106654). The lack of a comparator group limits the validity of these findings; it is unclear how tomato juice consumption compared with the natural resolution of radiation dermatitis. More evidence is needed to rate tomato for these uses.

VITAMIN A

EFFECTIVE

Vitamin A deficiency. Oral vitamin A is effective for treatment and prevention of vitamin A deficiency. Details: Clinical and observational research in children shows that taking vitamin A orally is effective for preventing and improving symptoms of vitamin A deficiency, including xerophthalmia, night blindness, and Bitot's spots (82329,82689,82710,90773). Vitamin A deficiency can occur due to abnormal storage and transport of vitamin A in people with abetalipoproteinemia, protein deficiency, diabetes mellitus, hyperthyroidism, fever, liver disease, and cystic fibrosis (7135). However, research suggests that supplementation with vitamin A may not be necessary for most newborns with vitamin A deficiency. An observational study in newborns with vitamin A levels of 0.43-0.59 mcmol/L or >0.59 mcmol/L found that vitamin A levels increased naturally over the first six months of life, regardless of oral vitamin A supplementation. However, in infants with very low vitamin A levels (<0.43 mcmol/L), vitamin A supplementation was associated with significant increases in vitamin A levels at 6 months of age when compared with no supplementation, suggesting that only newborns with very low vitamin A levels should receive oral vitamin A (107298).

Aging skin. Topical vitamin A (retinol) formulations seem to improve symptoms of aging skin, such as wrinkles and mottled pigmentation. Details: The vitamin A analog tretinoin (Renova) is a prescription drug approved by the U.S. Food and Drug Administration for adjunctive use in reducing fine wrinkles, hyperpigmentation, and tactile roughness of aging facial skin (103711). However, this drug is not interchangeable with non-prescription, commercially available vitamin A products, which have not been as extensively evaluated in clinical research. Although research evaluating non-prescription topical vitamin A shows benefit for reducing wrinkles, most studies have been small and used different formulations. One small study in adults over 40 years of age shows that applying a pea size amount of 0.075% retinol cream to the face daily for 26 weeks seems to reduce deep and fine wrinkling when compared with placebo. Applying a lower dose of 0.04% retinol cream for 13 weeks seems to reduce fine wrinkling to a lesser degree, with no effect on deep wrinkles, when compared with placebo cream (104458). Another small clinical study in adults over 80 years of age shows that applying 2 mL of retinol 0.4% lotion to the upper arm up to 3 times weekly for 24 weeks reduces visible wrinkles when compared with placebo (94683). Two small studies in females ages 33 to 65 show that applying retinol 0.15%, 0.3% and 0.5% in liquid crystal formulation once daily to the face for 2-3 months improves skin pigmentation, elasticity, and wrinkles when compared with baseline (103680,104464). The validity of these two studies is limited by the lack of a comparator treatment. Topical vitamin A is frequently combined with other ingredients in commercial formulations; however these combinations have rarely been studied. A small clinical study in adults over 35 years with skin aging shows that applying a cream containing retinol 0.5%, niacinamide, resveratrol, and hexylresorcinol seems to improve wrinkling and skin tone when compared with baseline (104455). Another small preliminary clinical trial in adults ages 35-65 years with periorbital lines and wrinkles shows that applying a cream containing retinol modestly improves dryness, puffiness, redness, and darkness when compared with baseline. The retinol was conjugated with lactic acid, and the cream contained other nutrient and herbal ingredients It was applied around the eyes each evening, sometimes used in combination with another product each morning (109747).
Bronchopulmonary dysplasia. Intramuscular vitamin A may reduce the risk of bronchopulmonary dysplasia (BPD) in very low birth weight infants when given at a dose of 5000 IU three times weekly for 28 days. Lower doses do not seem to be effective. It is unclear if enteral vitamin A is beneficial for BPD. Details: A meta-analysis of 6 clinical trials in premature infants shows that intramuscular administration of vitamin A every other day or three times weekly for 28 days reduces the risk of BPD by around 33% when compared with control (107297). The results from this meta-analysis are primarily driven by a modestly sized clinical trial in very low birth weight infants which shows that intramuscular administration of vitamin A 5000 IU three times weekly for 28 days reduces the risk of BPD by 15% when compared with a sham control (82195). A subgroup analysis of this trial suggests that infants with the lowest BPD risk estimate based on gestational age, birth weight, sex, ethnicity, and oxygen levels 24 hours after birth appear to benefit more from vitamin A therapy than those with higher BPD risk estimates (107296). Previous research in this area utilized a lower dose of only 2000 IU every other day for 28 days, and showed no significant improvement in the rate of BPD (82331,82613). The evaluation of a higher dose was prompted by research noting that the lower doses evaluated in these earlier studies were unable to achieve serum retinol concentrations above 25 mcg/dL, while doses at or above 5000 IU three times weekly could reach this level (82731). Enteral vitamin A has also been investigated. Meta-analyses of two clinical trials show that supplementation with vitamin A at an average of 5,000 IU daily, staring within four days of birth, does not reduce the incidence of BPD when compared with placebo (109750,109753).
Diarrhea. Vitamin A seems to reduce the incidence of diarrhea in young children. However, it is unclear if oral vitamin A while breastfeeding is beneficial for preventing diarrhea in nursing infants. Details: A meta-analysis of clinical research in children up to age 5 shows that vitamin A supplementation reduces the incidence of diarrhea by 15% and mortality related to diarrhea by 12% when compared with control, usually placebo or no supplementation (109755). However, one small clinical trial in breastfeeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of diarrhea in the nursing infants when compared with placebo (107293).
Measles. High-dose oral vitamin A seems to reduce mortality from measles in children under 2 years of age and may also reduce the incidence of measles in children up to 5 years of age. Details: Meta-analyses of clinical research show that taking vitamin A does not reduce mortality in children with measles when all ages and/or doses are considered (82373,82502,95055,109755). However, in children with measles who are less than 2 years of age, taking vitamin A 200,000 IU orally for at least two doses seems to reduce mortality by up to 83% when compared with placebo (82373,82502). Also, taking vitamin A seems to reduce the incidence of measles in children ages 6 months to 5 years (95055,109755).
Night vision. Oral vitamin A as retinyl palmitate seems to reduce night blindness during pregnancy in malnourished patients. Details: Clinical research shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before and during pregnancy reduces pregnancy-related night blindness by 37% in malnourished patients (6154). Some evidence suggests that zinc supplements might potentiate the effects of vitamin A in restoring sight in zinc-deficient pregnant patients affected by night blindness (8630).
Oral leukoplakia. High-dose oral vitamin A seems to reduce oral leukoplakia lesions in patients that chew tobacco and/or betel nut. Details: Clinical research in patients with tobacco and/or betel nut chewing habits shows that taking oral vitamin A 200,000-300,000 IU weekly for 6-12 months seems to result in remission of leukoplakia lesions in over 50% of participants when compared with placebo (34674,82617). However, it is unknown if vitamin A prevents the development of oral cancer from oral leukoplakia lesions.
Overall mortality. In children at risk for vitamin A deficiency, oral vitamin A seems to reduce mortality. However, it does not seem to reduce mortality in healthy adults. Details: Despite previous debate on whether the programs supplying high-dose vitamin A in low- and middle-income countries with prevalent vitamin A deficiency are safe and effective for reducing child mortality, most experts, including World Health Organization, recommend high-dose vitamin A supplementation for those children (95055,95724,97170,109755). In 2010, a meta-analysis of 17 trials involving over 194,000 patients, showed that vitamin A supplementation reduces all-cause mortality by about 24% in children 6 months to 5 years of age (82559). However, some research published after this meta-analysis shows conflicting results (90773,90777). In fact, the largest clinical trial conducted to date (Deworming and Enhanced Vitamin A; DEVTA), which was published after the analysis and involved one million preschool children, suggests that high-dose vitamin A supplementation does not reduce mortality (90773). However, this trial was limited due to under-resourcing and undetermined patient consent and treatment compliance (90773). Furthermore, in 2017, a meta-analysis including the DEVTA trial along with 46 additional studies involving over 1.2 million preschool children, shows that vitamin A supplementation does reduce all-cause mortality by 12% when compared with control (95055). This meta-analysis was updated in 2022 with no additional studies or changes in conclusions (109755). Adult mortality is not reduced by vitamin A supplementation. In fact, some evidence even shows that vitamin A supplementation increases mortality when administered to healthy adult patients or those with a stabilized disease (15305,34622,90775).
Postpartum complications. Oral vitamin A seems to reduce postpartum diarrhea and mortality in malnourished patients. Details: A large clinical study in malnourished pregnant patients in Nepal shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before, during, and after pregnancy reduces the occurrence of blood and mucus in the stool by 93% and the occurrence of diarrhea by up to 90% during the first 6 months postpartum when compared with placebo (2581). Another clinical study in the same population shows that taking vitamin A (as retinyl palmitate) 23,000 IU weekly before and during pregnancy reduces pregnancy-related mortality by 40% when compared with placebo (6153).
Retinitis pigmentosa. Oral vitamin A supplementation in children with retinitis pigmentosa seems to slow retinal function decline. Details: Observational and clinical research in children with retinitis pigmentosa shows that taking an age-adjusted dose of vitamin A, up to a maximum dose of 15,000 IU daily, modestly attenuates the decline in retinal function when compared with control (83,97167,103677).
Ulcerative colitis. Oral vitamin A supplementation in patients with ulcerative colitis seems to improve clinical response and mucosal healing. Details: A clinical study in adults with symptomatic ulcerative colitis despite treatment with 5-aminosalicylic acid shows that taking vitamin A 25,000 IU daily for 2 months reduces disease severity and increases the rate of clinical response and mucosal healing when compared with placebo. The number needed to treat (NNT) for clinical response is 3; the NNT for mucosal healing is 5 (100329).
Wrinkled skin. Topical vitamin A (retinol) formulations seem to improve photodamage and wrinkles. Details: The vitamin A analog tretinoin (Renova) is a prescription drug approved by the U.S. Food and Drug Administration for adjunctive use in reducing fine wrinkles, hyperpigmentation, and tactile roughness of facial skin (103711). This drug is not interchangeable with non-prescription, commercially available vitamin A products, which have not been as extensively evaluated in clinical research. Still, some research in females ages 35-65 with moderately wrinkled and photoaged skin suggests that commercially available retinol formulations might reduce wrinkles and skin roughness similarly to tretinoin. One study used retinol serum starting at a concentration of 0.25% and increased to 1% over 3 months, compared with tretinoin cream 0.025% gradually increased to 0.1% (103671), while another study compared a gradual release tri-retinol 1.1% cream applied daily for 3 months to tretinoin 0.025% cream (104456). Commercial retinol also seems to be beneficial when compared with placebo. A small study in adults over 40 years old with photodamaged skin shows that applying stabilized retinol 0.1% to the face daily for one year improves wrinkles and mottled pigmentation in over 50% of the participants when compared with a placebo treatment (104463).

Atopic disease. Supplementation with oral vitamin A does not seem to reduce the risk of atopy. Details: Clinical research in infants born in Guinea-Bissau shows that a single dose of vitamin A does not reduce the incidence of atopy when compared with placebo (90779,90780). Furthermore, giving a single dose of vitamin A to some infants, such as low birth weight infants and infants given Bacille Calmette-Guerin (BCG) vaccination, was associated with increased atopy and wheeze (90779).
Fetal and premature infant mortality. Giving oral vitamin A to malnourished adults during pregnancy and postpartum does not seem to reduce fetal, early infant, or first year mortality. Giving oral or intramuscular vitamin A to the infant also does not seem to reduce mortality in most patients. Details: Most meta-analyses of clinical research in malnourished patients suggest that vitamin A supplementation during pregnancy or postpartum does not reduce fetal, early infant, or first year mortality (6152,34601,34602,34627,82479,82566,82567,90774,90776,90782,90784,95057,109750,109753). Also, giving vitamin A supplements or intramuscular vitamin A to low birth weight infants does not appear to reduce mortality in these patients (82195,82431,82498,90778,90781,95053,107296,107297). Furthermore, vitamin A supplementation in term infants from low or middle income countries also does not appear to reduce the risk of mortality at 6 or 12 months of age when compared with placebo (95054,103674). Some evidence from a meta-analysis of clinical research shows that vitamin A supplementation may reduce the risk of mortality at 6 months in Asian infants, although it appears to increase the risk of mortality at 6 months in studies conducted in Africa. It also appears to increase the risk of mortality in female term infants by 12 months (95054).
Intestinal parasite infection. Oral high-dose vitamin A does not seem to prevent reinfection with intestinal parasites. Details: Clinical research in children living in Malaysia that were given albendazole 400 mg daily for 3-4 days for parasitic worms, shows that adding a single dose of vitamin A 200,000 IU does not help to prevent reinfection when compared with placebo (90772).
Melanoma. Oral vitamin A in patients with resected melanoma does not seem to improve survival and disease recurrence. Details: A clinical study in patients with completely resected melanoma shows that taking vitamin A 100,000 IU daily for 18 months does not increase disease-free survival when compared with no supplementation (82670).
Miscarriage. Oral vitamin A given to the mother does not prevent miscarriage or stillbirth. Details: A meta-analysis of clinical research shows that maternal supplementation with oral vitamin A, either alone or in combination with other vitamins, prior to or during early pregnancy does not reduce the risk of miscarriage or stillbirth when compared with control (104462).
Sepsis. Most research shows that oral vitamin A does not reduce the risk of sepsis in premature infants. Details: A meta-analysis of three clinical trials in premature infants shows that providing supplemental enteral vitamin A 1500-5000 IU daily, starting within four days of birth, does not reduce the incidence of sepsis when compared with placebo (109753).
Tuberculosis. Oral vitamin A does not seem to improve tuberculosis disease duration or mortality. Details: Low levels of vitamin A are common in patients with tuberculosis. However, taking vitamin A 2000 IU to 200,000 IU by mouth for 2-24 months does not improve symptoms, decrease disease duration, or reduce mortality when compared with placebo in these patients (82570,103668,109754). This may be due to the fact that vitamin A levels may normalize following the initiation of tuberculosis treatment, even without additional vitamin A supplementation.

LIKELY INEFFECTIVE

Head and neck cancer. Oral vitamin A taken for 2 years does not seem to improve survival or prevent head and neck cancer recurrence. Details: A large clinical study n patients with a history of head and neck cancer shows that taking vitamin A as retinyl palmitate 300,000 IU daily for 1 year, and followed by 150,000 IU daily for another year, does not reduce the risk of second primary tumors or tumor recurrence when compared with placebo. Also, vitamin A does not seem to improve survival or event-free survival (1710).
HIV transmission. Oral vitamin A does not reduce vertical HIV transmission risk. There is some concern that vitamin A might increase HIV transmission through breast milk. Details: Observational and intervention research shows that taking vitamin A orally does not decrease the risk of HIV transmission to the fetus during pregnancy, to newborns during delivery, or to infants during early breast-feeding (6376,82470,95059). Preliminary clinical research also shows that vitamin A supplementation of pregnant adults with HIV infection might increase the risk of HIV transmission to their babies through breast milk (9801).
Lower respiratory tract infections. Oral vitamin A does not reduce the risk for lower respiratory tract infections in children. It is unclear if supplementation of oral vitamin A while breast-feeding reduces the risk of lower respiratory tract infections in nursing infants. Details: Taking vitamin A by mouth does not prevent or reduce symptoms of lower respiratory tract infections, such as cough and fever, in children (82288,82443). Furthermore, some research shows that vitamin A is associated with a slight increase in the risk of respiratory tract infections when administered to children with adequate nutritional status (82288). Additionally, one small clinical trial in breast-feeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of febrile illness or respiratory tract infections in the nursing infants when compared with placebo (107293).

Acne. Although prescription vitamin A analogs are approved to treat acne, it is unclear if non-prescription topical vitamin A products help with acne symptoms. Details: The high-dose vitamin A analogs adapalene (Differin) and tazarotene (Tazorac) are prescription drugs approved by the US Food and Drug Administration for the treatment of acne (103712,103713). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol, which have not been extensively evaluated in clinical research. A small preliminary clinical trial in adolescents and young adults with mild to moderate acne shows that applying topical benzoyl peroxide 2.5% each morning and a topical retinol plus salicylic acid product each evening for 12 weeks modestly improves acne severity and other measures of complexion when compared with baseline. All patients also used the same cleanser twice daily (109748). The validity of this finding is limited by the lack of a comparator group.
Alcohol-related liver disease. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with acute alcoholic hepatitis shows that taking vitamin A in combination with coenzyme Q10 and other vitamins and minerals daily for 6 months does not improve survival when compared with placebo (61392).
Asthma. It is unclear if oral vitamin A is beneficial for preventing asthma in children. Details: An observational study in children has found that higher dietary intake of vitamin A is associated with a lower risk of asthma. Children in the highest quartile of vitamin A intake (median of 2267 IU daily) at 7 years of age had improved lung function and 32% lower odds of asthma at 11-14 years of age when compared with children in the lowest quartile of vitamin A intake (median of 870 IU daily) (107291).
Atopic dermatitis (eczema). It is unclear if supplementation of oral vitamin A while breast-feeding is beneficial for preventing eczema in nursing infants. Details: One small clinical trial in breast-feeding parents shows that supplementation of vitamin A 1800 IU and ergocalciferol (vitamin D2) 600 IU daily for 2 months does not reduce the risk of eczema in the nursing infants when compared with placebo (107293).
Autism spectrum disorder. It is unclear if oral vitamin A is beneficial for improving symptoms of autism. Details: Children with autism spectrum disorder are at increased risk for vitamin A deficiency, and vitamin A levels have been inversely associated with autism symptoms. Preliminary clinical research shows that taking a single dose of vitamin A 200,000 IU slightly improves emotional response, communication, and other symptoms when compared to baseline (97168). The lack of a control group limits the validity of these findings. Another preliminary clinical study in children with autism and vitamin A deficiency shows that taking vitamin A 50,000 IU weekly for 6 months, but not as a single dose of 200,000 IU, seems to improve social impairment scores when compared with control. Controls were children with autism without vitamin A deficiency that did not take a supplement (104459).
Breast cancer. Although vitamin A intake has been associated with a reduced risk for breast cancer, it is unclear if vitamin A supplements are beneficial. Details: Epidemiological evidence has found an association between high intake of vitamin A and a reduced risk of breast cancer. A meta-analysis of epidemiological research has found that the adults with the highest intake of vitamin A, either from diet alone or also from supplements, reduces the odds of developing breast cancer by 16% when compared with the lowest intake (1444,34610,109752). However, the effects of supplemental vitamin A, specifically, are unclear.
Cataracts. It is unclear if oral vitamin A is beneficial for cataract prevention. Details: A large-scale population-based study has found that high dietary intake of vitamin A is associated with a reduced risk of nuclear cataracts (6378). Also, other population research has found that the highest dietary intake of vitamin A is associated with a 17% lower risk of cataracts when compared with the lowest intakes (90786). However, there is conflicting evidence regarding the association between blood levels of vitamin A and the risk of cataracts (90786,90944). It is not known if supplemental vitamin A is beneficial.
Cervical cancer. It is unclear if oral vitamin A is beneficial for cervical cancer prevention. Details: A meta-analysis of clinical research shows that increased vitamin A levels in the blood or higher vitamin A intakes are associated with a reduced risk of cervical cancer. However, this effect is observed when both forms of vitamin A, either retinol or carotenoids, are considered. When only the retinol form is considered, vitamin A supplementation does not seem to reduce the risk of cervical cancer (34613,109752). Also, a meta-analysis of epidemiological research has found that vitamin A intake, either from diet alone or supplements, does not affect the risk of cervical cancer (109752).
Chemotherapy-induced diarrhea. It is unclear if oral vitamin A helps to prevent diarrhea caused by chemotherapy. Details: A very small clinical study in children receiving chemotherapy shows that taking vitamin A orally does not seem to prevent GI adverse effects, including diarrhea and mouth pain, when compared with control (9802).
Child development. Oral vitamin A might improve growth and development in children with vitamin A deficiency, but not in those with good nutritional status. Details: Supplementing with vitamin A 60 mg for up to 9 years does not promote or improve child growth in children with appropriate nutritional status (20132). However, in children with vitamin A deficiency, supplementation with vitamin A may improve growth (82246).
Chronic obstructive pulmonary disease (COPD). There is limited evidence on the oral use of vitamin A in patients with emphysema. Details: Observational research has found that consuming recommended amounts of vitamin A in the diet is associated with 33% lower odds of developing emphysema (103678).
Colorectal adenoma. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination supplement containing selenium, zinc, vitamin A, vitamin C, and vitamin E orally daily for 5 years or until the recurrence of an adenoma reduces the risk of recurrent large-bowel adenomas by about 40% when compared with placebo in patients with large-bowel adenomas (92903). It is not clear if this benefit is due to vitamin A or other constituents.
Colorectal cancer. It is unclear if oral vitamin A is beneficial for colorectal cancer prevention. Details: Taking vitamin A alone or in combination with beta-carotene does not seem to reduce the risk of colorectal cancer (12185).
Coronary artery bypass graft (CABG) surgery. It is unclear if oral vitamin A improves recovery after CABG surgery. Details: Preliminary clinical research shows that taking vitamin A 5000 IU daily (as retinol palmitate) for 21 days starting on the day of CABG surgery reduces time in intensive care after surgery by 46% to 69% compared to a control group not given vitamin A (90783). Supplementation with vitamin A also improves total hospitalization time for those patients with adequate zinc status (90783).
Coronavirus disease 2019 (COVID-19). It is unclear if oral vitamin A is beneficial for the treatment of mild to moderate COVID-19. Details: Clinical research in COVID-19 outpatients treated with hydroxychloroquine shows that taking vitamin A 25,000 IU daily for 10 days modestly reduces the number of patients with symptoms of fever, body ache, and fatigue when compared with placebo. However, there was no effect on the number of patients with cough, shortness of breath, lack of appetite, chest pain, diarrhea, loss of smell, or headache (109745).
Depression. It is unclear if oral vitamin A is beneficial for depression. Details: A meta-analysis of observational research has found that dietary intake of vitamin A is inversely associated with depression. The highest intake of vitamin A was associated with a 17% reduced risk of depression when compared with the lowest intake. Also, vitamin A intake was lower in individuals with depression (109743). The effect of vitamin A supplementation is unclear.
Esophageal cancer. It is unclear if oral vitamin A is beneficial for esophageal cancer prevention. Details: Observational research has found that higher beta-carotene and vitamin A intake is associated with a reduced risk of esophageal cancer (34551,103675). However, evidence from higher-quality clinical research shows that taking vitamin A in combination with beta-carotene does not reduce the risk of esophageal cancer (12185).
Gastric cancer. It is unclear if oral vitamin A is beneficial for gastric cancer prevention. Details: Taking vitamin A alone and in combination with beta-carotene does not seem to reduce the risk of gastric cancer (12185).
Glaucoma. It is unclear if oral vitamin A is beneficial for glaucoma prevention. Details: A meta-analysis of observational research has found that a high dietary intake of vitamin A is associated with a 37% reduced risk of glaucoma when compared with a low intake (109742).
HIV/AIDS. It is unclear if oral vitamin A is beneficial for improving HIV/AIDs outcomes. Details: A meta-analysis of clinical trials and population research shows that maternal vitamin A supplementation of mothers with poor vitamin A status at baseline does not influence child or maternal mortality, hospitalization rate, or HIV/AIDS progression. However, pediatric vitamin A supplementation seems to decrease mortality rates in children with HIV/AIDS when compared with placebo (34529,95059).
HIV/AIDS-related diarrhea. It is unclear if oral vitamin A is beneficial for preventing diarrhea associated with HIV. Details: A large clinical trial shows that taking vitamin A can decrease the rate of diarrhea-specific mortality by up to 92% in vitamin A-deficient children with or without HIV/AIDS (1465). However, a meta-analysis of clinical research shows that taking vitamin A does not significantly reduce diarrhea-specific mortality when only children with HIV/AIDS are considered (82511). But vitamin A does appear to reduce overall mortality in these children by 50% to 63% (1465,82511).
Human papillomavirus (HPV). It is unclear if topical or oral vitamin A is beneficial for the resolution of genital warts caused by HPV. Details: A meta-analysis of small clinical trials in patients with genital warts suggests that the oral prescription drugs isotretinoin and etretinate might promote resolution of warts when compared with baseline. However, the topical prescription drug tretinoin 0.05% cream does not seem to help (104460). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol.
Infant development. It is unclear if intramuscular vitamin A improves the development of low birth weight infants. Details: A meta-analysis of clinical research shows that giving intramuscular vitamin A to very low birth weight infants reduces the risk of chronic lung disease at 36 weeks postmenstrual age by about 13% compared to control (95053). Preliminary clinical research also shows that giving intramuscular vitamin A along with inhaled nitric oxide gas for 3 weeks to low birth weight infants on mechanical ventilation might improve mental development at one year in some of these patients when compared with inhaled nitric oxide gas alone (90778). However, a meta-analysis of clinical research shows that intramuscular vitamin A does not improve neurodevelopment in very low birth weight infants (95053).
Iron deficiency anemia. It is unclear if oral vitamin A is beneficial for the prevention or treatment of anemia due to iron deficiency. Details: Some research in children and pregnant adults without anemia shows that taking vitamin A increases plasma levels of hemoglobin and ferritin, and may reduce the risk of developing anemia (9518,34627). However, another study in pregnant patients, half of whom had anemia at baseline and half of whom did not have anemia, shows that taking 3000 mcg retinol orally in combination with iron and folate does not improve hemoglobin or erythropoietin concentrations when compared with taking iron and folate (9188). In preterm infants with existing anemia, taking vitamin A 5000 IU and vitamin B complex 40 mg daily improves serum ferritin, hemoglobin, and reticulocyte levels and reduces the need for blood transfusions when compared with taking either vitamin alone. Taking vitamin A alone, however, does not improve these outcomes (100330).
Leukemia. It is unclear if oral vitamin A is beneficial for leukemia prevention. Details: Preliminary clinical research in adults with chronic myelogenous leukemia shows that taking a specific vitamin A product (Aquasol, Armour Pharmaceuticals) 50,000 IU orally daily in combination with busulfan therapy does not significantly increase progression-free survival or overall survival when compared with busulfan alone. Furthermore, supplementation with vitamin A plus busulfan seems to increase the percentage of patients who experience grade 2 toxicity by about 5-fold when compared with busulfan alone (82652).
Liver cancer. It is unclear if oral vitamin A is beneficial for liver cancer prevention. Details: Population research has found that vitamin A supplementation or serum levels of vitamin A are not associated with the risk of liver cancer (97169).
Lung cancer. It is unclear if oral vitamin A is beneficial for lung cancer treatment or prevention. Details: Population research has found that increased dietary intake of vitamin A is not associated with a reduced risk of lung cancer (35628). Furthermore, supplementation with vitamin A and beta-carotene seems to increase the risk of lung cancer in smokers or those exposed to asbestos (2642,34675). A large clinical trial in patients with existing lung cancer shows that vitamin A 300,000 IU daily for one year followed by 150,000 IU daily for a second year does not increase survival (1710). However, some clinical research shows that high-dose vitamin A 300,000 IU daily following curative lung cancer resection reduces the risk of new primary tumors in patients heavily exposed to tobacco (7875).
Malaria. It is unclear if oral vitamin A is beneficial for reducing symptoms of malaria in young children. Details: Taking vitamin A orally seems to help decrease symptoms of malaria in children less than 3 years of age living in endemic areas (1464). However, other clinical research shows that single doses of vitamin A 100,000 to 200,000 IU do not improve coma resolution, convulsions, fever, parasite clearance, or mortality in infants and children less than 5 years of age with cerebral malaria (90785).
Multiple sclerosis-related fatigue. It is unclear if oral vitamin A is beneficial for reducing fatigue in patients with multiple sclerosis. Details: Preliminary clinical research in patients with relapsing-remitting multiple sclerosis receiving interferon beta-1a shows that taking vitamin A 25,000 IU (as retinyl palmitate) (Zahravi Pharmaceutical) daily for 6 months followed by 10,000 IU daily for 6 months, improves physical, cognitive, and psychosocial fatigue when compared with placebo (95052).
Necrotizing enterocolitis (NEC). A meta-analysis of several small clinical trials suggests that intramuscular vitamin A does not seem to prevent NEC. Details: A meta-analysis of 3 small clinical studies in very low birth weight infants shows that intramuscular administration of vitamin A 1500-5000 IU every other day or three times weekly for 28 days does not reduce the risk of NEC when compared with a control (107297).
Non-Hodgkin lymphoma. It is unclear if oral vitamin A is beneficial for non-Hodgkin lymphoma prevention. Details: Population research has found that intake of vitamin A at levels above 2330 mcg daily is associated with a 17% lower risk of non-Hodgkin lymphoma when compared with those whose daily intake of vitamin A is less than 642 mcg per day (90945).
Nonmelanoma skin cancer. It is unclear if oral vitamin A is beneficial for nonmelanoma skin cancer prevention. Details: Observational research over 26 years found that higher dietary vitamin A intake is associated with a 12% reduced risk for cutaneous squamous cell carcinoma in healthy patients when compared with lower vitamin A intake (101673).
Oral clefts. It is unclear if oral vitamin A is beneficial for oral cleft prevention. Details: A meta-analysis of observational research has found that periconceptional use of vitamin A, from diet and/or supplements, is associated with a 13% reduced incidence of cleft lip alone or with a cleft palate, but is not associated with the risk of cleft palate alone, in the child (109751).
Osteoarthritis. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with osteoarthritis shows that taking a specific product containing vitamin A in combination with selenium, vitamin C, and vitamin E (Selenium ACE, Carls-Berghs Farmaceutiska AB) does not appear to alleviate symptoms when compared with placebo (74449).
Ovarian cancer. It is unclear if oral vitamin A is beneficial for ovarian cancer prevention. Details: Most observational research has found that increased dietary intake of vitamin A is associated with a reduced risk of developing ovarian cancer (9193,103679,109752). The most recent meta-analysis of epidemiological research has found that adults with the highest intake of vitamin A, either from diet alone or supplements, reduces the odds of developing ovarian cancer by 19% when compared with the lowest intake (109752).
Pancreatic cancer. It is unclear if oral vitamin A is beneficial for pancreatic cancer prevention. Details: A meta-analysis of observational research has found that higher intake of vitamin A is associated with a reduced risk of pancreatic cancer; however, this benefit appears to be limited to only hospital-based cases and studies conducted in Europe (95060). In contrast, a meta-analysis of clinical research shows that taking vitamin A in combination with beta-carotene does not reduce the risk of pancreatic cancer (12185).
Parkinson disease. It is unclear if oral vitamin A prevents Parkinson disease development. Details: Population research has found that blood levels or dietary intake of vitamin A are not associated with the risk of Parkinson disease (91164).
Photoreactive keratectomy. Oral vitamin A has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking a specific product (Evitex capsules, Alcon) containing vitamin A along with vitamin E seems to improve healing after photoreactive keratectomy. High dose (50,000 to 75,000 IU) vitamin A in the form of retinol palmitate taken daily with vitamin E (alpha-tocopheryl nicotinate) 460-590 mg daily seems to accelerate re-epithelialization, reduce haze formation, and improve visual acuity in patients undergoing laser surgery for myopia (348).
Pneumonia. Oral vitamin A does not seem to prevent mortality related to pneumonia in children. However, it is unclear if vitamin A reduces symptom severity and hospitalization in children. Details: Clinical research in children living in developing countries shows that taking vitamin A orally does not prevent mortality related to pneumonia (1466,82362,82504,82717,109749). However, the evidence related to symptom duration and severity is mixed. A large study and early meta-analyses show that vitamin A does not prevent pneumonia or decrease the severity or length of hospitalization in children with pneumonia (1466,82362,82504,82717). A more recent meta-analysis also shows that giving vitamin A to children at or below 5 years of age does not affect the duration of hospitalization (109755). The best evidence to date comes from a recent meta-analysis of randomized clinical trials. This meta-analysis shows that, when given in combination with conventional therapy to children up to 10 years of age, vitamin A reduces the duration of symptoms including fever, cough, lung rale, and shortness of breath, as well as the duration of hospitalization and time to a negative X-ray, when compared with conventional therapy alone (109749). However, the number of trials evaluating each endpoint is small and more research is needed to confirm these findings.
Prematurity. It is unclear if vitamin A reduces the duration of hospitalization for premature infants. Details: A meta-analysis of four randomized controlled trials in preterm infants shows that providing supplemental enteral vitamin A 1500-5000 IU daily, starting within four days of birth, does not reduce the duration of hospitalization when compared with placebo (109750).
Prostate cancer. It is unclear if oral vitamin A is beneficial for prostate cancer prevention. Details: Observational studies suggest that dietary intake of vitamin A is not associated with a reduced risk of prostate cancer (14134).
Psoriasis. It is unclear if topical vitamin A is beneficial for psoriasis symptoms. Details: The vitamin A analog tazarotene (Tazorac) is a prescription drug that is approved by the U.S. Food and Drug Administration to treat stable plaque psoriasis covering up to 20% body surface area (103713). This drug is not interchangeable with non-prescription, commercially available vitamin A products, such as retinol.
Radiation proctopathy. It is unclear if oral vitamin A is beneficial for reducing chronic radiation proctopathy symptoms. Details: A small clinical study in patients experiencing chronic radiation proctopathy caused by pelvic radiotherapy shows that taking retinol palmitate 10,000 IU daily for 90 days might reduce rectal symptoms when compared with placebo (82350).
Retinopathy of prematurity. Most small studies show that oral or intramuscular vitamin A does not reduce the risk of retinopathy of prematurity (ROP). Details: A meta-analysis of 4 small clinical studies in very low birth weight infants shows that intramuscular administration of vitamin A 2000-10,000 IU every other day or three times weekly, or oral vitamin A 2000 IU daily, for 28 days does not reduce the risk of ROP when compared with a control (107297). Another meta-analysis of clinical research shows that providing supplemental enteral vitamin A 1500 IU or an average of 5000 IU daily, starting within four days of birth, does not reduce the incidence of severe ROP (109750,109753). However, a very small clinical study in preterm infants, which was not included in the meta-analysis, shows that receiving retinol palmitate drops 3000 IU/kg daily for 28 days reduces the risk of ROP by 88% when compared with no treatment (103672).
Urinary tract infections (UTIs). It is unclear if adding oral vitamin A to antibiotic therapy is beneficial for symptoms of acute pyelonephritis in young females. Details: A small clinical study in females 2-12 years of age with a first occurrence of acute pyelonephritis shows that taking vitamin A 1500 units/kg daily for 10 days in conjunction with antibiotics decreases the duration of fever by about 1.3 days and reduces urinary frequency by about 1.5 episodes per day when compared to taking placebo with antibiotics. Taking vitamin A might also reduce the occurrence of moderate or severe renal scarring after 6 months when compared with placebo (100327). The validity of these findings is limited by small study size and a high dropout rate.
Warts. It is unclear if topical or oral vitamin A improves the resolution of viral warts. Details: A meta-analysis of observational and clinical research in patients with viral warts suggests that receiving prescription oral retinoids (isotretinoin, acitretin, etretinate) seems to produce a 61% rate of wart resolution. Prescription topical retinoids seems to produce a 64% rate of wart resolution (104461). These drugs are not interchangeable with non-prescription, commercially available vitamin A products, such as retinol. More evidence is needed to rate vitamin A for these uses.

VITAMIN E

EFFECTIVE

Ataxia with vitamin E deficiency (AVED). Oral vitamin E is effective for treating vitamin E deficiency due to the genetic disorder AVED. Details: This genetic disorder occurs when the gene that produces alpha-tocopherol transfer protein (alpha-TTP) is defective. This causes severe vitamin E deficiency. Symptoms such as cerebellar ataxia, dysarthria, absence of deep tendon reflexes, and sensory loss usually appear between 4 and 18 years of age. Vitamin E supplements are used in the treatment of AVED (13498,101437,101438).
Vitamin E deficiency. Oral vitamin E is effective for preventing or treating vitamin E deficiency and associated conditions. Details: Taking vitamin E orally is effective for preventing and treating vitamin E deficiency (4844). However, vitamin E deficiency is rare in humans. It most commonly occurs in people with malabsorption disorders such as abetalipoproteinemia; cystic fibrosis; gastrectomy; hepatic-biliary tract disease including chronic cholestasis, hepatic cirrhosis, biliary atresia, and obstructive jaundice; in infants receiving formula with insufficient vitamin E; intestinal diseases including celiac and tropical sprue; and regional enteritis (4844,104411).

Alzheimer disease. Oral vitamin E might slow functional decline in some patients with this condition. However, it does not seem to prevent Alzheimer disease onset. Details: A clinical study in patients with moderate Alzheimer disease shows that taking all-rac-alpha-tocopherol (synthetic vitamin E) 2000 IU daily for 2 years might be similar to selegiline (Eldepryl), and superior to placebo, for slowing cognitive decline. Benefit was only apparent when outcomes were adjusted for baseline Mini-Mental State Examination (MMSE) scores. This study is limited by attrition bias, or incomplete outcome reporting (4635,97070). Another clinical study in patients with mild-to-moderate Alzheimer disease shows that taking all-rac-alpha-tocopherol 2000 IU daily reduces the annual rate of decline in activities of daily living by 19% when compared with placebo. This translates to a delay in disease progression of 6.2 months. This is comparable to the effect of acetylcholinesterase inhibitors (e.g., rivastigmine) in this population. Despite these positive findings, the World Health Organization (WHO) recommends against the use of vitamin E for the management of dementia due to the increased risk for adverse effects with the extended use of high-dose vitamin E (104823). Interestingly, the combination of vitamin E and memantine (Namenda) 20 mg per day is not superior to placebo in this population. Researchers speculate that this lack of effectiveness may be due to an interaction between vitamin E and memantine, but this proposed interaction has not been validated in research (19060,97070). Vitamin E supplementation doesn't seem to prevent Alzheimer disease or slow progression of mild cognitive impairment. Patients with mild cognitive impairment who take vitamin E 2000 IU daily for 3 years progress to Alzheimer disease at the same rate as those who take placebo (13060,97070). Furthermore, although population research has found that greater intake of foods high in vitamin E is associated with a lower risk of developing Alzheimer disease (34597,90082), taking vitamin E supplements does not seem to help. Evidence from a large clinical study that was later converted into an observational study shows that taking vitamin E 400 IU orally daily does not prevent Alzheimer disease when compared with placebo in cognitively intact men (93570). However, this study is limited by the fact that the participants were well-educated and were assessed for dementia in their 60s; the prevalence of dementia is typically low in this age group (93571).
Beta-thalassemia. Oral vitamin E seems to be beneficial for children with this condition. Details: A small clinical study in children with beta-thalassemia and low vitamin E plasma concentrations shows that taking vitamin E orally seems to correct erythrocyte membrane abnormalities when compared with control (4642). Another small clinical trial in children 5-18 years of age with beta-thalassemia shows that taking an age-based dose of vitamin E (alpha-tocopherol) 200-600 mg daily for 4 weeks seems to increase haptoglobin levels, suggesting reduced hemolysis, when compared with placebo (104412).
Dysmenorrhea. Oral vitamin E seems to reduce pain in adults with dysmenorrhea. Details: Small clinical studies in younger adults with primary dysmenorrhea show that taking vitamin E 200-500 IU daily, starting 2 days before menstruation and continuing through the first 3 days of bleeding for 2-4 cycles, decreases the severity and duration of pain and reduces blood loss when compared with placebo (10361,14432,99367). One study also shows that taking vitamin E 200 IU with fish oil provides better pain relief when compared with taking either vitamin E or omega-3 fatty acids alone (99367). A meta-analysis of 8 small clinical studies, including those described above, in individuals with dysmenorrhea shows that taking vitamin E reduces the severity of pain when compared with placebo (112170).
Exercise-induced muscle damage. Oral vitamin E seems to modestly reduce exercise-induced muscle damage. Details: A meta-analysis of 17 very small clinical studies in trained and untrained adults shows that taking vitamin E 300-1200 IU daily for up to 12 weeks reduces markers of exercise-induced muscle damage, including creatine kinase and lactate dehydrogenase, when compared with placebo. Vitamin E appears to be most beneficial in athletes and at doses under 500 IU daily (112160). However, a small clinical study in endurance-trained runners, not included in the analysis above, shows that taking vitamin E (as alpha-tocopherol) 235 mg and vitamin C 1000 mg 2 hours prior to an exercise protocol does not reduce delayed onset muscle soreness or improve markers of exercise-induced muscle damage when compared with placebo (109961).
Glucose-6-phosphate dehydrogenase (G6PD) deficiency. Oral vitamin E seems to be beneficial in patients with G6PD deficiency. Details: Individual clinical studies evaluating the use of vitamin E in patients with G6PD deficiency show mixed results (4682,4683,4684). However, a meta-analysis of 6 small clinical studies in patients with G6PD deficiency shows that taking vitamin E improves hemoglobin levels and reduces reticulocyte levels when compared with placebo in the setting of both acute and chronic hemolysis (112164).
Intracranial hemorrhage. Oral vitamin E might reduce the risk of intracranial hemorrhage in premature infants. Details: Clinical research shows that giving premature neonates vitamin E orally might reduce the risk of intracranial hemorrhage when compared with control (4655,85074).
Intraventricular hemorrhage. Oral vitamin E might reduce the risk of intraventricular hemorrhage in premature infants. Intravenous vitamin E does not provide this benefit. Details: A meta-analysis of the available clinical research shows that oral, but not intravenous, administration of vitamin E can reduce the risk for intraventricular hemorrhage in premature neonates when compared with control. However, it might not reduce the risk for severe (grade III-IV) intraventricular hemorrhage. Additionally, high serum levels of vitamin E have been associated with an increased risk for sepsis in premature infants (85062).
Nitrate tolerance. Oral vitamin E might reduce tolerance to nitrates. Details: Nitrate tolerance might involve increased vascular superoxide anion production, and antioxidants may help prevent this (4705). Clinical research in patients with ischemic heart disease shows that taking vitamin E 447-894 IU daily can help prevent nitrate tolerance when compared with placebo (4705,11543).
Nonalcoholic steatohepatitis (NASH). Oral vitamin E seems to improve outcomes in patients with NASH. Details: Clinical studies and meta-analyses in adults with NASH shows that taking vitamin E 800 IU daily for up to 24 months improves liver enzymes, hepatic fibrosis, steatosis, and lobular inflammation (14005,17517,97077,104413). Taking vitamin E 400-1200 IU in children with NASH also seems to improve liver enzyme levels after 4-10 months of treatment (89). Furthermore, a small study in patients with NASH shows that taking vitamin E 800 IU daily for 1 year seems to improve liver histology to a similar degree as taking telmisartan 40 mg daily (104405). In fact, practice guidelines by the American Association for the Study of Liver Diseases (AASLD) recommend taking vitamin E 800 IU daily as a first-line therapy in non-diabetic adults with biopsy-proven NASH. However, vitamin E isn't recommended in NASH patients with diabetes, cirrhosis, or cryptogenic cirrhosis (98130).
Premenstrual syndrome (PMS). Oral vitamin E seems to improve PMS symptoms. Details: Clinical research in adults with PMS shows that taking vitamin E 400-600 IU daily for 3 cycles reduce subjective reports of symptoms, including anxiety, craving, and depression, when compared with placebo (4719,4720). Another small clinical study in Japanese patients with PMS shows that taking vitamin E, as gamma-tocopherol 180 mg, twice daily for 7 days during the luteal phase of 2 consecutive cycles reduces fatigue, irritability, and leg swelling when compared with placebo (112337).
Tardive dyskinesia. Oral vitamin E might attenuate worsening of tardive dyskinesia in patients taking antipsychotic medications. Details: Small clinical studies suggest that taking vitamin E orally improves Abnormal Involuntary Movement Scale (AIMS) scores in patients with tardive dyskinesia. It seems to be more effective in higher doses and in people who have had tardive dyskinesia for less than 5 years (3942,3943,3944,3945,3946,3948,85323). Both RRR-alpha-tocopherol (natural vitamin E) and unspecified forms were used in clinical trials. However, some conflicting findings have been reported. A meta-analysis suggests that vitamin E does not improve symptoms of tardive dyskinesia when compared with placebo; however, taking vitamin E seems to prevent the deterioration of symptoms when compared with placebo (97079).

Age-related macular degeneration (AMD). Oral vitamin E does not seem to slow AMD progression. Details: Results from clinical trials and meta-analyses of clinical trials show that vitamin E when taken alone or in combination with other antioxidants does not prevent the development (4667,7303,7304,34625) or progression of AMD (34633). In contrast, taking vitamin E 400 IU orally with elemental zinc 80 mg, vitamin C 500 mg, and beta-carotene 15 mg daily does seem to be beneficial. When taken for 5 years, this combination reduces visual acuity loss and reduces the risk of progression of AMD by 25% in patients with advanced AMD (7303,11326). A 10-year follow-up on this study confirmed these findings (90069). It is not known if this combination is beneficial for people with less advanced macular disease or for preventing AMD. Additionally, it is not clear if this benefit is due to vitamin E, the other ingredients, or the combination.
Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Oral vitamin E does not seem to slow ALS progression. Details: Clinical research in patients with ALS shows that taking alpha-tocopherol 1490 IU daily for up to 12 months in addition to riluzole does not influence survival or motor function when compared with riluzole alone. However, these patients seem to be less likely to progress to a more severe disease state from a milder disease state (83180). Additionally, a large population study has found that dietary intake of vitamin E is not associated with risk of developing ALS (90087).
Angina. Oral vitamin E does not seem to reduce angina symptoms. Details: Clinical research shows that taking vitamin E orally may have some effect on endothelial dysfunction, but does not improve angina in nonsmokers or smokers, when compared with placebo (3896,4634,4649,4650,4651,4652).
Atherosclerosis. Oral vitamin E does not seem to reduce atherosclerosis progression. Details: Taking RRR-alpha-tocopherol (natural vitamin E) orally does not appear to have any effect on atherosclerosis progression or mortality in patients with atherosclerosis when compared with placebo (3899,3936). However, there is preliminary evidence that a combination of vitamin E and vitamin C might help prevent the progression of atherosclerosis in men, particularly smokers and cardiac transplant patients (1918).
Atopic dermatitis (eczema). Oral vitamin E does not seem to reduce eczema symptoms. Details: Clinical research shows that taking vitamin E 600 IU in combination with selenium daily for 12 weeks does not improve symptoms of atopic eczema when compared with placebo or selenium alone (74456). Also, while some clinical research shows that taking 600 IU of all-rac-alpha-tocopherol (synthetic vitamin E) daily for 60 days with vitamin D 1600 IU improves overall atopic dermatitis symptoms, pruritus, and erythema when compared with placebo, taking vitamin E alone does not seem to have this effect. However, vitamin E alone does improve hard, leathery skin symptoms and dryness when compared with placebo (84491).
Breast cancer-related hot flashes. Oral vitamin E does not seem to reduce hot flashes related to breast cancer. Details: Clinical research shows that taking vitamin E 800 IU daily for 4 weeks does not reduce hot flashes in females who have had breast cancer when compared with placebo (454).
Bronchopulmonary dysplasia. Oral vitamin E does not seem to reduce the risk for bronchopulmonary dysplasia in premature infants. Details: Clinical research in premature infants weighing less than 1500 grams at birth shows that taking vitamin E orally does not prevent bronchopulmonary dysplasia when compared with placebo (4657,85062).
Cataracts. Oral vitamin E does not seem to reduce cataract risk. Details: Some population research has found that dietary and supplemental vitamin E intake is associated with a reduced risk of developing age-related cataracts (4208,4663,4665,4759). However, other population research has not found this association (2395,4664,92902). Additionally, higher quality evidence from clinical trials and a meta-analysis consistently shows that vitamin E, taken alone or with other vitamins, does not prevent the progression of age-related cataracts or decrease vision loss when compared with control (4666,7304,34626).
Chemotherapy-induced peripheral neuropathy. Oral vitamin E does not seem to reduce peripheral neuropathy due to chemotherapy. Details: Although some small, low-quality clinical studies and a meta-analysis of these studies suggest that vitamin E 600 mg daily for 3 months might be beneficial for preventing chemotherapy-induced peripheral neuropathy induced by cisplatin, carboplatin, or oxaliplatin when compared with placebo (10366,85117,90072), these studies have found no effect with lower doses of vitamin E or in those receiving paclitaxel chemotherapy (107862). In addition to the low methodological quality of the studies, the validity of these finding is limited by high heterogeneity, as the studies included patients with several different cancer types. Also, a large, high-quality clinical study shows that taking vitamin E 400 mg daily is not beneficial for preventing peripheral neuropathy induced by taxanes or platinum analogues when compared with placebo (101457). The American Society of Clinical Oncology does not recommend the use of vitamin E for the prevention or management of chemotherapy-induced peripheral neuropathy (101434).
Colorectal cancer. Oral vitamin E does not seem to reduce colorectal cancer risk. Details: Some population research has found that intake of vitamin E and multivitamins is associated with a reduced risk of colorectal cancer (1047). Some preliminary clinical research also shows that taking vitamin E orally in combination with other vitamins might have a protective effect in patients with a history of colorectal adenomas (3954,3956,92903). However, higher quality evidence from larger clinical trials and meta-analyses of clinical research consistently show that taking vitamin E supplements alone, or in combination with other vitamins, does not prevent colorectal cancer incidence or recurrence when compared with control (3953,3955,3957,12185,13036,13131,34594,90361). Despite this conflicting research, the US Food and Drug Administration (FDA) approved a qualified health claim in 2009 regarding vitamin E and colorectal cancer risk. However, the FDA has determined that it is highly unlikely that vitamin E supplements reduce the risk of colorectal cancer (102332).
Congestive heart failure (CHF). Oral vitamin E does not seem to reduce CHF symptoms or prevent CHF development. Details: Clinical research in adults with New York Heart Association (NYHA) functional class III or IV heart failure shows that taking vitamin E (RRR- α tocopherol) 500 IU orally daily for 12 weeks does not improve prognostic or functional indices of CHF or quality of life measurements when compared with placebo (3906). Additionally, population research shows that taking vitamin E 600 IU every other day does not affect the risk of developing heart failure in healthy females 45 years or older when compared with placebo (90068).
Head and neck cancer. Oral vitamin E does not seem to reduce the risk of head and neck cancer recurrence. In fact, it might increase recurrence risk. Details: A large clinical trial in patients with stage I or II head and neck cancer shows that taking all-rac-alpha-tocopherol (synthetic vitamin E) 400 IU daily, during radiation therapy and for 3 years after the end of radiation therapy, does not reduce the risk of recurrence of the first tumor or development of a second primary tumor when compared with placebo. In fact, there is some concern that patients taking vitamin E seem to have an increased risk of tumor recurrence or a second primary tumor when compared with patients taking placebo (13055). Advise patients with head and neck cancer to avoid taking vitamin E supplements in doses of 400 IU/day or more.
Hypertension. Oral vitamin E does not seem to reduce blood pressure. Details: A clinical study in patients with hypertension who are receiving conventional treatment shows that taking vitamin E 300 mg daily orally for 3-4 years does not lower blood pressure when compared with control (5210).
Intrauterine growth restriction (IUGR). Oral vitamin E during pregnancy does not seem to reduce IUGR risk. Details: A meta-analysis of clinical research shows that taking vitamin E along with other ingredients throughout pregnancy does not reduce the risk for IUGR when compared with placebo (97075).
Liver disease. Oral vitamin E does not seem to reduce liver disease-associated mortality. Details: A meta-analysis of clinical research shows that taking vitamin E does not reduce all-cause-or liver related-mortality or morbidity in patients with liver diseases, including autoimmune liver diseases, viral hepatitis, alcoholic liver disease, or cirrhosis (34608). Additional clinical research in male smokers over 50 years old shows that taking vitamin E 75 IU orally, alone or with beta-carotene 20 mg orally, daily for 5-8 years does not reduce the risk of mortality due to chronic liver disease when compared with placebo (91383).
Oral leukoplakia. Oral vitamin E does not seem to reduce the risk for oral leukoplakia in male smokers. Details: Although there is some conflicting evidence (3951,4708), the largest randomized controlled trial indicates that supplementation with all-rac-alpha-tocopherol (synthetic vitamin E) 55.6 IU daily for 5-7 years has no effect on the incidence of oral lesions in male cigarette smokers when compared with placebo (3951).
Osteoarthritis. Oral vitamin E does not seem to be beneficial for osteoarthritis treatment or prevention. Details: Taking vitamin E 500 IU daily for 6 months does not seem to decrease symptoms of pain or stiffness in patients with osteoarthritis when compared with placebo (5264). Additional clinical research show that taking vitamin E 500 IU daily for up to 2 years does not slow cartilage loss when compared with placebo (13066). Population research has shown that taking vitamin E supplements does not reduce the risk of developing osteoarthritis or slow the progression of existing osteoarthritis (5881).
Pancreatic cancer. Oral vitamin E does not seem to reduce pancreatic cancer risk. Details: Taking vitamin E supplements alone or in combination with other antioxidants such as beta-carotene and vitamin C does not reduce the risk of developing pancreatic cancer (12185,85147). Taking all-rac-alpha-tocopherol (synthetic vitamin E) 55.6 IU daily for 5 to 8 years also does not seem to reduce the incidence of or mortality from carcinoma of the pancreas in male smokers (3961).
Parkinson disease. Oral vitamin E does not seem to reduce Parkinson disease symptoms or progression, although the risk of developing the disease may decrease with increased dietary vitamin E intake. Details: Observational research has found that dietary vitamin E intake might be associated with a decreased occurrence of Parkinson disease (4712). A meta-analysis of 12 studies evaluating the risk of developing Parkinson disease has found that the highest daily intake of vitamin E is associated with a 20% lower risk than those with the lowest intake (107858). However, clinical research in patients with stage I or II Parkinson disease shows that taking all-rac-alpha-tocopherol (synthetic vitamin E) 2000 IU daily for up to 24 months doesn't seem to have any benefit when compared with baseline or control (4709,4710,4711,85318).
Pharyngeal cancer. It is unclear if oral vitamin E reduces the risk of developing cancer of the pharynx. Details: A sub-group analysis of a large-scale clinical trial (The HOPE Trial) in patients with diabetes or cardiovascular disease suggests that taking RRR-alpha-tocopherol (natural vitamin E) 400 IU daily for about 7 years is not linked with a reduced risk of developing oral or pharyngeal cancer when compared with placebo (13036).
Pre-eclampsia. Oral vitamin E does not seem to reduce pre-eclampsia risk. Details: The majority of clinical research shows that taking a combination of vitamins E and C, at the same doses, does not reduce the risk of pre-eclampsia in low-, moderate-, or high-risk patients, when compared with placebo or no treatment. Also, the risk of gestational hypertension might increase in some cases, although results are inconsistent (83312,83356,83383,83472,83474,97075,97059). Other researchers using vitamin E in combination with vitamin C and allopurinol beginning at 24-32 weeks gestation found the combination similar to placebo (4718). However, some clinical research suggests that taking a combination of vitamin E 400 IU and vitamin C 1000 mg daily reduces the risk of proteinuric hypertension in high-risk patients when started in weeks 16-22 of pregnancy (3236).
Preterm labor. Oral vitamin E does not seem to reduce risk for premature labor. Details: A meta-analysis of clinical research shows that taking vitamin E along with other ingredients throughout pregnancy does not reduce the risk for preterm labor when compared with placebo (97075).
Prostate cancer. Oral vitamin E does not seem to reduce the risk of prostate cancer. Details: A meta-analysis of over 30 large clinical trials and observational studies shows that neither dietary nor supplemental vitamin E reduces the risk of prostate cancer when compared with a control (112159). However, individual study results are mixed. Population research on the use of dietary or supplemental vitamin E intake for prostate cancer risk reduction is conflicting (12872,14124,12873,15607). Although one large-scale study in smokers found that taking 55.6 IU daily of all-rac-alpha-tocopherol (synthetic vitamin E) reduced the risk of prostate cancer and mortality (3959,11303), most large-scale randomized, controlled trials show that vitamin E is not beneficial. A sub-group analysis of a large-scale clinical study (The HOPE trial) in patients with diabetes or cardiovascular disease suggests that taking 400 IU of RRR-alpha-tocopherol (natural vitamin E) daily for about 7 years is not linked with a decreased risk of developing prostate cancer when compared with placebo (13036). Another large scale study (Physician's Health Study II) shows that taking vitamin E 400 IU every other day for an average of 8 years does not reduce the risk of prostate cancer when compared with placebo (16708,90097). Similarly, another large clinical study (The SU.VI.MAX study) shows that a combination of vitamin E (alpha-tocopherol) 44.7 IU, vitamin C 120 mg, beta-carotene 6 mg, selenium 100 mcg, and zinc 20 mg daily for an average of 8 years does not reduce the risk of prostate cancer overall when compared with placebo (14135). A fourth large-scale clinical trial (The SELECT trial) in men over the age of 50 years shows that taking all-rac-alpha-tocopherol (synthetic vitamin E) 400 IU daily, alone or in combination with selenium 200 mcg daily, for an average of about 5.5 years does not reduce prostate cancer risk when compared with placebo (16707). Also, an extension of this initial study found that taking vitamin E alone was associated with a 17% increased of developing prostate cancer (17688).
Respiratory tract infections. Oral vitamin E does not seem to reduce respiratory infections in most patients. However, there's some evidence that it might reduce incidence of the common cold in patients living in long-term care facilities. Details: Taking oral vitamin E 298 IU daily, alone or in supplemental multivitamin form, does not appear to decrease the incidence, duration, or severity of upper or lower respiratory infections in elderly persons when compared with placebo (10788,12094). However, some research shows that taking vitamin E reduces the incidence of the common cold in elderly long-term care patients when compared with placebo (12094). More evidence is needed to determine how effective vitamin E might be for reducing the incidence of the common cold.
Retinitis pigmentosa. Oral vitamin E does not seem to reduce retinitis pigmentosa and related visual decline. Details: Taking all-rac-alpha-tocopherol (synthetic vitamin E) orally does not appear to slow visual decline is people with retinitis pigmentosa and has been associated with more rapid loss of visual acuity, although the validity of the study with these findings has been questioned (83,84,85,86,87,88).
Scarring. Topical vitamin E does not seem to improve scar appearance. Details: Some clinical research shows that applying ointment containing vitamin E topically does not reduce surgical wound scarring when compared with a placebo ointment (4721,4722).
Stillbirth. Oral vitamin E does not seem to reduce risk of a stillborn baby. Details: A meta-analysis of clinical research shows that taking vitamin E along with other ingredients during pregnancy does not reduce the risk for stillbirth when compared with placebo (97075).

LIKELY INEFFECTIVE

Breast cancer. Oral vitamin E does not reduce breast cancer risk. Details: Some evidence suggests that higher serum levels of vitamin E might be associated with a reduced risk of breast cancer (10132). However, increasing vitamin E intake from the diet or supplements does not seem to reduce the risk of developing breast cancer (4658,4659,85147,112334). Also, a large-scale randomized trial in patients with diabetes or cardiovascular disease shows that patients who take 400 IU of RRR-alpha-tocopherol (natural vitamin E) daily do not have a reduced risk of developing breast cancer (13036). In other large-scale studies, females who take RRR-alpha-tocopherol (natural vitamin E) 600 IU every other day for up to 10 years also do not have a lower risk of developing breast cancer (13131,34580).
Cancer. Oral vitamin E does not reduce the risk of cancer in most patients. Details: Some research suggests that a combination of vitamin E 44.7 IU daily with vitamin C, beta-carotene, selenium, and zinc does not lower the overall risk of cancer, although it might reduce the risk of cancer when only males are evaluated (14109). However, clinical research from a large scale study (Physician's Health Study II) shows that taking vitamin E 400 IU every other day for an average of 8 years does not reduce the overall risk of cancer in males when compared with placebo (16708,90097). Also, clinical research published in a meta-analysis shows that taking vitamin E does not reduce the overall risk of cancer (85147). In 2003, the US Food and Drug Administration (FDA) approved a qualified health claim regarding antioxidant vitamins, such as vitamin E and overall cancer risk. However, the FDA has determined that the evidence is limited and inconclusive (102334). The US Preventive Services Task Force (USPSTF) states that there is no net benefit to supplementation with vitamin E for the prevention of cancer in general and therefore recommends against its use (108641,112166).
Cardiovascular disease (CVD). Most evidence shows that oral vitamin E does not reduce the risk for CVD events or complications. Details: Most clinical research in various populations shows that taking vitamin E supplements orally is not effective for preventing heart disease or adverse cardiovascular outcomes such as myocardial infarction (MI), stroke, hospitalizations for unstable angina, morbidity, or cardiovascular death (12492,12493,13036,14108,66140,83050,85084,85224). The US Preventive Services Task Force (USPSTF) states that there is no net benefit to supplementation with vitamin E for the prevention of CVD in general and therefore recommends against its use (108641,112166). With few exceptions (3357,3936), large-scale controlled clinical trials show that vitamin E supplements offer no benefit for primary prevention in healthy or high-risk patients (3907,3935,3937,13036,13131), or for secondary prevention of heart disease and cardiovascular events such as MI, stroke, and death (3896,3899,13036). While one analysis of clinical research found that in mostly healthy patients 70 years or younger without CVD, vitamin E supplementation reduces the risk of cardiovascular mortality, the authors performed more than 20 statistical tests and did not adjust for multiple comparisons. Therefore, it possible that the positive effect was due to chance. This analysis was also limited because it excluded adults older than 70 years of age and adults that are more likely to suffer an exacerbation from a chronic condition. Furthermore, the analysis showed that vitamin E supplementation does not reduce the risk of all-cause mortality or the risk of CVD compared with placebo or no intervention (97078). There's additional conflicting evidence. One large-scale trial shows that healthy females who take RRR-alpha-tocopherol (natural vitamin E) 600 IU every other day for up to 10 years also do not have a lower risk of major cardiovascular events but might have a 24% lower risk of cardiovascular death when compared with placebo (13131). This finding is contradictory to previous findings. One notable limitation of this trial is a lack of systematic assessment of the use of statins or other cardiovascular therapies by the participants throughout the 10-year period. Meta-analyses of clinical trials involving patients with type 2 diabetes and the haptoglobin 2-2 genotype show that taking vitamin E, up to 600 IU daily for up to 8 years, reduces the incidence of non-fatal myocardial infarction and death due to CVD (85179,85221). Because these meta-analyses included only specific patients, the generalizability of the results is questionable. There is debate about whether some forms of vitamin E might work differently than others. Some people suggest that RRR-alpha-tocopherol (natural vitamin E) is more effective than all-rac-alpha-tocopherol (synthetic vitamin E). This has not been verified by studies. A meta-analysis of vitamin E studies indicates that there is no significant difference in cardiovascular outcomes based on the form of vitamin E used (13132). The FDA has refused to allow labeling claims for vitamin E supplements for prevention of CVD (3939). A Science Advisory from the American Heart Association also states that the evidence doesn't justify use of antioxidants such as vitamin E for reducing the risk of CVD (12142). Advise patients not to rely on vitamin E supplements for preventing heart disease.
Fetal and premature infant mortality. Oral vitamin E does not seem to reduce death in preterm infants. Details: Meta-analyses of clinical research show that taking vitamin E throughout pregnancy does not affect morbidity or mortality in preterm infants when compared with placebo (85074,97075).
Fibrocystic breast disease. Oral vitamin E does not improve fibrocystic breast disease in most patients. Details: Clinical research shows that taking alpha-tocopherol 150 IU, 300 IU, or 600 IU daily for 2-3 months does not improve subjective or objective measures of fibrocystic breast disease when compared with placebo (4660,4661,4662).
Lung cancer. Oral vitamin E does not seem to reduce lung cancer risk. Details: Taking all-rac-alpha-tocopherol (synthetic vitamin E) 55.6 IU daily for 5-8 years is not associated with a lower risk of developing lung cancer for male smokers (3949). A sub-group analysis of a large scale clinical trial in patients with diabetes or cardiovascular disease who take RRR-alpha-tocopherol (natural vitamin E) 400 IU daily for about 7 years do not have a lower risk of developing lung cancer when compared with placebo (13036). In another large-scale study, females who take RRR-alpha-tocopherol (natural vitamin E) 600 IU every other day for up to 10 years also do not have a lower risk of developing lung cancer (13131). Meta-analyses of clinical research suggest taking vitamin E as alpha-tocopherol for up to approximately 10 years does not prevent lung cancer or reduce the incidence of lung cancer mortality when compared with placebo (34632,85147).
Overall mortality. Oral vitamin E does not seem to reduce the risk of mortality from all causes. Details: Although some population research suggests that increased dietary vitamin E intake is associated with reduced overall mortality (98260), most meta-analyses of clinical research in adults show that taking vitamin E supplements for at least 1 year does not affect all-cause mortality (34622,85164,85200). Furthermore, when only high quality clinical trials were analyzed, mortality was increased by 3% in adults taking vitamin E when compared with control (34622).
Prematurity. Oral vitamin E does not seem to reduce the risk of premature birth and complications. Details: Clinical research shows that vitamin E does not improve blood parameters or prevent the development of anemia in premature infants (4648,10362). One clinical study in premature infants weighing less than 1500 grams at birth shows that giving vitamin E 25 IU daily for six weeks does not improve hemoglobin concentration, reticulocyte counts, or platelet counts when compared with placebo (4648). Another clinical study in premature infants weighing less than 1250 grams at birth shows that giving vitamin E 50 IU daily for eight weeks does not increase the response to erythropoietin and iron when compared with placebo (10362).

Aging skin. Topical vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in Asian females aged 30-65 years shows that applying a specific liquid product, (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) containing vitamin E 1%, vitamin C 20%, and red raspberry leaf cell culture extract 0.0005%, to the face nightly for 8 weeks, in addition to regular facial skin products, improves skin color, elasticity, radiance, smoothness, and appearance of wrinkles when compared with regular facial skin products alone (102355).
Anemia of chronic disease. Small clinical studies suggest that oral vitamin E might improve response to anemia treatment in patients on chronic hemodialysis. Details: Two small studies in adults and children on chronic hemodialysis have shown improved response to erythropoietin with vitamin E supplementation (4640,4647). In one study, children given vitamin E 22.4 IU/kg in combination with erythropoietin had significantly increased hemoglobin and hematocrit levels after 2 weeks of combination treatment, compared with eight and five weeks in patients receiving erythropoietin alone (4640). In a study of adults, concurrent supplementation with vitamin E 745 IU daily allowed dose reductions of erythropoietin from an average of 93 U/kg/week to 74 U/kg/week with the same resultant hemoglobin levels (4647).
Anthracycline cardiotoxicity. Oral vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with breast cancer receiving doxorubicin and cyclophosphamide chemotherapy shows that taking vitamin E 600 mg three times daily and L-carnitine 3000 mg by intravenous infusion on day 1 followed by 300 mg by mouth four times daily thereafter for 3 weeks reduced the risk of cardiovascular events by 63% and improved laboratory markers of cardiotoxicity when compared with chemotherapy alone (112338). It is unclear if these findings are due to vitamin E, L-carnitine, or the combination.
Anxiety. It is unclear if oral vitamin E is beneficial in patients with anxiety. Details: A meta-analysis of 5 mostly small clinical studies in patients without anxiety shows that taking vitamin E 200-400 IU daily for up to 10 weeks does not improve anxiety symptom scores when compared with placebo (112158). It is unclear if these findings can be generalized to patients with anxiety disorders.
Asthma. It is unclear if oral vitamin E is beneficial for asthma treatment or prevention. Details: There is inconsistent evidence about the role of vitamin E in asthma. Some population research has found that increased dietary intake of vitamin E is associated with a lower risk of asthma; however taking vitamin E supplements are not associated with decreased risk (6058,15006). Low vitamin E intake also appears to be associated with an increased risk of asthma (315,401,422). A small clinical study in children with asthma suggests that adding vitamin E 74.5 IU by mouth daily to fluticasone treatment for 8 weeks may decrease cough, wheezing, and dyspnea when compared with baseline (90077). This study was limited because it did not compare the vitamin E intervention to the control group.
Atopic disease. It is unclear if oral vitamin E reduces the risk of atopic disease in infants. Details: Population research has found that increased maternal vitamin E intake isn't associated with decreased odds of developing eczema, food allergy, wheeze, allergic sensitization, or any allergic disease in infants (90098).
Bladder cancer. It is unclear if oral vitamin E reduces bladder cancer risk. Details: A meta-analysis of clinical research shows that the highest intake of vitamin E is associated with a reduced risk for bladder cancer when compared to the lowest intake in patients followed for more than 10 years. This benefit was not seen in those followed for less than 10 years. This effect appears to be dose-dependent, although it is not clear how much vitamin E intake is required to reduce bladder cancer risk. Additionally, it is not clear whether this benefit differs for dietary or supplemental intake of vitamin E (101435). In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding vitamin E and bladder cancer risk. However, the FDA has determined that it is highly unlikely that vitamin E supplements reduce the risk of bladder cancer (102332). Some population research also shows that regular use of vitamin E supplements for more than 10 years is associated with a reduced risk of bladder cancer mortality; however, use for less than 10 years is not associated with reduced mortality (9839).
Burns. It is unclear if topical vitamin E is beneficial for healing of burn wounds. Details: A small clinical study in patients with moderate and deep burn wounds (25% to 67%) shows that applying a specific alpha-tocopherol product (Filme Olio) daily seems to reduce infection and improve healing when compared with usual treatment (104407).
Chemotherapy-related infection. It is unclear if oral vitamin E is beneficial in patients with infection due to chemotherapy. Details: Observational research suggests that greater dietary intake of vitamin E may lower the incidence of infection in children undergoing chemotherapy for lymphoblastic leukemia (11997).
Chronic fatigue syndrome (CFS). Although there is interest in using oral vitamin E for CFS, there is insufficient reliable information about the clinical effects of vitamin E for this condition.
Cisplatin-associated ototoxicity. It is unclear if oral vitamin E is beneficial for preventing ototoxicity due to cisplatin. Details: A small clinical study in patients receiving cisplatin for solid tumors shows that taking a specific vitamin E supplement (Rigentex, Bracco) as alpha-tocopherol 400 IU daily for 3 months attenuates hearing loss when compared with placebo (97082).
Colistin-induced nephrotoxicity. It is unclear if oral vitamin E is beneficial for preventing nephrotoxicity due to colistin. Details: A small clinical study in patients receiving colistin therapy shows that taking vitamin E (alpha-tocopherol) 400 IU orally daily for the duration of colistin therapy does not reduce the incidence or duration of acute kidney injury when compared with colistin alone (107867).
Contrast induced nephropathy. It is unclear if oral or intravenous vitamin E is beneficial in patients with nephropathy due to contrast dye. Details: A small clinical study in patients receiving elective computer-assisted tomography with nonionic radiocontrast agents shows that receiving vitamin E 3218 IU emulsion in 0.45% saline intravenously infused at the rate of 1 mL/kg/hr over 24 hours does not decrease the risk of contrast agent-induced nephropathy when compared with normal saline alone (90081). However, oral vitamin E may modestly reduce the risk of contrast induced nephropathy. A clinical trial shows that taking vitamin E as alpha-tocopherol 522 IU or gamma-tocopherol 447 IU orally daily, starting 5 days prior to the procedure and continuing 2 days post-procedure, results in a 9% to 10% lower incidence of contrast induced acute kidney injury when compared with standard treatment with normal saline (90096). Another clinical study shows that taking a single dose of vitamin E 1490 IU orally before elective coronary angiography reduces the risk of contrast induced kidney injury by 7% when compared with placebo (97074).
Coronary artery bypass graft (CABG) surgery. It is unclear if oral vitamin E is beneficial for recovery after CABG. Details: When taking vitamin E orally with vitamin C and allopurinol two days prior to CABG and one day postoperatively, patients had fewer perioperative infarctions and lower creatine kinase-MB release (4699); however, this benefit was not found when using vitamin E alone or in combination with vitamin C without allopurinol (4697,4698).
Critical illness (trauma). An analysis of several small clinical studies suggests that oral or intravenous vitamin E is not beneficial in patients admitted to the intensive care unit (ICU). Details: A meta-analysis of 5 small clinical studies in patients admitted to the ICU shows that administration of oral or intravenous vitamin E 400-3000 IU daily for up to 4 weeks does not decrease the length of hospital or ICU stay or reduce the risk of mortality when compared with control (112335). The validity of these findings is limited by a high degree of heterogeneity among the studies, which included differences in vitamin E dosing, duration of therapy, and reasons for ICU admission.
Dementia. It is unclear if oral vitamin E is beneficial for dementia prevention; the available research is conflicting. Details: A longitudinal cohort study in Japanese adults aged 40 years or older at baseline who were followed for a median of about 20 years, shows that total daily dietary intake of vitamin E is inversely associated with the risk of developing dementia, with a hazard ratio of about 0.8 for the highest compared with lowest quartiles of intake (107857). In a longitudinal cohort study of males aged 71-93 years, consuming supplemental vitamin E and vitamin C decreased the risk of developing vascular and mixed or other dementias; however, there was no protective effect for Alzheimer dementia (4636). Evidence from clinical research that evolved into an observational study shows that taking vitamin E 400 IU daily does not decrease the incidence of dementia in males 60 years or older (93570). However, the results from this study are limited by selection bias due to the high education levels and relatively young age of the participants, limitations with case ascertainment, and problems with follow-up (93570,93571). Also, these studies did not distinguish between different forms of vitamin E (4636,93570).
Depression. It is unclear if oral vitamin E is beneficial in patients with depression. Details: A meta-analysis of 7 mostly small clinical studies in patients without major depressive disorder shows that taking vitamin E 400-2000 IU daily for up to 6 months modestly improves depression symptom scores when compared with placebo (112158). It is unclear if these findings can be generalized to patients with depression.
Developmental coordination disorder (DCD). Oral vitamin E has only been evaluated in combination with other ingredients for DCD; its effect when used alone is unclear. Details: A small clinical study in children with developmental coordination disorder (DCD), also known as dyspraxia, shows that taking vitamin E orally, in combination with evening primrose oil, thyme oil, and fish oils, for 4 months seems to improve movement when compared with control (5708). The effects of vitamin E alone on DCD are unclear.
Diabetes. It is unclear if oral vitamin E is beneficial for the treatment or prevention of diabetes. Details: Population research has found that higher vitamin E dietary intake is associated with a lower risk of developing type 2 diabetes (14004). However, individual clinical studies in patients with existing diabetes show mixed results (13496,13497,90095,90099,98259). A meta-analysis of 36 small clinical studies in patients with diabetes suggests that vitamin E may slightly improve some measures of glycemic control. In patients with type 2 diabetes, vitamin E seems to reduce glycated hemoglobin (HbA1c) by around 0.2% and improve insulin resistance, but not fasting blood glucose, when compared with placebo. In patients with type 1 diabetes, vitamin E seems to reduce HbA1c by around 0.8%, but does not improve fasting blood glucose, when compared with placebo (112161). The validity of this analysis is limited by a high degree of heterogeneity across the studies, including differences in vitamin E dose, treatment duration, concomitant medications, patient populations, and study designs.
Diabetic foot ulcers. Oral vitamin E has only been evaluated in combination with other ingredients for diabetic foot ulcers; its effect when used alone is unclear. Details: A small clinical study in adults with a grade 3 diabetic foot ulcer shows that taking vitamin E 400 IU and magnesium oxide 250 mg daily for 12 weeks reduces ulcer length, width, and depth when compared with placebo (101436). A small clinical study in adults with non-healing diabetic foot ulcers being treated with a platelet-rich plasma fibrin glue dressing shows that taking vitamin E 200 IU and vitamin C 12.5 mg orally twice daily for 8 weeks increases the rate of ulcer healing when compared with placebo. In those receiving vitamins, 46% of wounds closed completely, compared with 17% of those receiving placebo (107870). It is not clear if the effects seen in these studies are due to vitamin E, the other nutrients, or the combinations.
Diabetic nephropathy. It is unclear if oral vitamin E is beneficial in patients with diabetes and impaired kidney function. Details: A meta-analysis of clinical research in adults with diabetic nephropathy shows that taking vitamin E 600-1200 mg daily, alone or with other antioxidants, modestly reduces urinary albumin excretion when compared with placebo or no treatment, but seems to have no effect on glomerular filtration rate (GFR) (97069). A small clinical study in patients with diabetic nephropathy shows that taking a specific tocotrienol-rich vitamin E supplement (Tocovid SupraBio, Hovid Nutriworld) 200 mg twice daily for 12 weeks seems to modestly reduce serum creatinine, with a corresponding increase in GFR, when compared with placebo. According to a sub-group analysis, these improvements remain statistically significant in patients with low tocopherol levels (less than 42 mcmol/L) at baseline, but not in those with higher levels at baseline (103010). Another small clinical study shows that taking this same supplement regimen for 12 months reduces serum creatinine levels and improves GFR at 8 months, but not 12 months, when compared with placebo. In a subgroup analysis of patients with stage 3 chronic kidney disease, these benefits persisted at 12 months when compared with placebo (107390).
Diabetic neuropathy. It is unclear if oral vitamin E is beneficial for improving diabetic neuropathy symptoms. Details: A small clinical trial in patients with uncontrolled type 2 diabetes and neuropathy shows that taking a specific vitamin E supplement (Evion) 400 IU daily for 12 weeks modestly decreases neuropathic pain scores when compared to baseline (90091). Another very small clinical trial shows that taking vitamin E 1341 IU daily for 6 months improves nerve conduction in diabetic neuropathy when compared with placebo (4724).
Down syndrome. Oral vitamin E does not seem to slow cognitive decline in patients with this condition. Details: A clinical study in patients over 50 years old with Down syndrome shows that taking vitamin E 1000 IU twice daily for 3 years does not slow cognitive decline when compared with placebo (97076).
Endometriosis. Oral vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with endometriosis and pelvic pain shows that taking vitamin E 800 IU and vitamin C 1000 mg daily for 8 weeks improves dysmenorrhea, dyspareunia, and chronic pelvic pain scores when compared with placebo (106622).
Extravasation. Topical vitamin E has only been evaluated in combination with dimethylsulfoxide (DMSO); its effect when used alone is unclear. Details: A very small clinical study in patients receiving chemotherapy shows that applying vitamin E topically, in combination with DMSO, seems to prevent skin ulceration after chemotherapy extravasation (4668).
Gastric cancer. It is unclear if oral vitamin E is beneficial for preventing gastric cancer or reducing associated mortality. Details: Population studies have found that increasing dietary vitamin E intake by 22.4 IU daily is associated with a 21% decreased risk of gastric cancer (3360,90083). However, clinical trials have not found that vitamin E supplements reduce gastric cancer risk (3960,4676,4677,12185). Studies evaluating vitamin E in combination with other supplements have been inconsistent. In one large-scale clinical trial a specific combination of vitamin E 100 IU with selenium 37.5 mcg and vitamin C 250 mg twice daily for about 7 years did not reduce risk of gastric cancer in patients from Shandong Province in China where there is a very high prevalence of gastric cancer (14447,90085). In another large-scale clinical study of 29,584 people in China, the combination of oral vitamin E, beta-carotene, and selenium over 5 years did reduce total mortality, total cancer mortality, and stomach cancer mortality (4679). A meta-analysis of clinical research shows that taking vitamin E plus beta-carotene with or without vitamin C does not reduce gastric cancer incidence (12185).
Glomerulosclerosis. It is unclear if oral vitamin E reduces proteinuria due to glomerulosclerosis in children. Details: A very small clinical study in children with focal segmental glomerulosclerosis who are refractory to standard medical management shows that taking vitamin E 200 IU daily orally might reduce proteinuria when compared with baseline (4675). The validity of this finding is limited by a lack of control group.
Granuloma annulare. Although there is interest in using topical vitamin E for granuloma annulare, there is insufficient reliable information about the clinical effects of vitamin E for this condition.
Helicobacter pylori. Oral vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in patients with Helicobacter pylori dyspepsia without ulcers shows that taking vitamin E 200 IU and vitamin C 500 mg by mouth twice daily for 30 days in addition to standard triple therapy increases eradication rates by 37% when compared with triple therapy alone (90094). It is not clear if this benefit is due to vitamin E, vitamin C, or the combination.
Huntington disease. It is unclear if oral vitamin E improves Huntington disease symptoms. Details: A small clinical study shows that taking RRR-alpha-tocopherol (natural vitamin E) might improve symptoms in patients with early Huntington disease, but this benefit is not seen in patients with more advanced disease when compared with placebo (4686).
IgA nephropathy. It is unclear if oral vitamin E is beneficial for IgA nephropathy in children. Details: A small clinical study in children with IgA nephropathy shows that taking vitamin E (400 IU for those weighing less than 30 kg; 800 IU for those weighing more than 30 kg) improves urinary protein to creatinine ratio, but not glomerular filtration rate, creatinine clearance, or hematuria, when compared with placebo (85063).
Infertility. It is unclear if oral vitamin E improves pregnancy rates in females with infertility of unknown cause. Details: A small clinical study in females experiencing implantation failure shows that taking vitamin E 400 IU daily for 12 weeks improves endometrial thickness when compared with placebo (99852). Vitamin E has also been studied in combination with selenium. In a small clinical study in patients with premature ovarian insufficiency (POI), taking vitamin E 400 IU with selenium 200 mcg orally daily for 90 days increases anti-Mullerian hormone index, antral follicle count, and mean ovarian volume after 12 months of follow-up when compared with placebo (107866). It is unclear if these improvements correlate to higher pregnancy or live birth rates.
Inflammatory bowel disease (IBD). Although there is interest in using oral vitamin E for IBD, there is insufficient reliable information about the clinical effects of vitamin E for this condition.
Insomnia. It is unclear if oral vitamin E is beneficial in patients with insomnia. Details: A moderate-sized clinical study in postmenopausal patients with chronic insomnia shows that taking vitamin E 400 IU daily for 1 month improves sleep quality ratings and reduces the need for sedative medications when compared with placebo (112163).
Intermittent claudication. It is unclear if oral vitamin E improves intermittent claudication symptoms. Details: A large clinical study in male smokers with intermittent claudication shows that taking all-rac-alpha-tocopherol (synthetic vitamin E) 50 mg orally daily for about 3.7 years does not appear to have any effect when used alone or in combination with beta-carotene for treating symptoms or disease progression when compared with placebo (4732). However, according to poor-quality clinical research included in a meta-analysis, taking vitamin E 447-2384 IU daily for up to 18 months appears to reduce symptoms of intermittent claudication (85023).
Lice. Topical synthetic vitamin E might be beneficial for head lice eradication. Details: A small clinical study in children and adults with head lice shows that topical application of a specific tocopheryl acetate 20% spray (LiceKO, Panin SRL) once, and then again 7 days later, is more effective for eliminating lice when compared with permethrin 1% cream rinse (90067).
Male infertility. An analysis of several small, low-quality clinical studies suggests that oral vitamin E might improve pregnancy rates and measures of sperm health in males with infertility. Details: Several small clinical studies in males with infertility show conflicting results (3583,4695,107865). However, a meta-analysis of 7 small, low-quality clinical trials shows that taking vitamin E 300-600 IU for 12-48 weeks increases pregnancy rates by 86% and modestly improves sperm count, concentration, motility, and vitality, but does not seem to increase semen volume, when compared with a control (109461). Vitamin E has also been used in combination with other nutrients with unclear results. Small studies show that taking vitamin E 800 mg daily with vitamin C 1000 mg daily for 8 weeks doesn't seem to improve sperm functionality (4696), while vitamin E 400 IU plus selenium 200 mcg daily for at least 100 days improves sperm functionality, but not fertilization rates, when compared with baseline (3585). In another small clinical study in infertile males undergoing varicocelectomy, taking vitamin E 400 IU, selenium 200 mcg, and folic acid 5 mg daily for 6 months improved sperm count and motility when compared with control (102968). Another small clinical study shows that taking vitamin E 100 mg and coenzyme Q10 10 mg three times daily for 3 months modestly increases levels of testosterone and improves progressive sperm motility and morphology when compared to baseline. However, taking an L-carnitine nutrient complex 15 grams twice daily was more effective for increasing testosterone and improving sperm parameters (109390). However, it is unclear if any of these combination therapies increases live birth rates.
Melanoma. It is unclear if oral vitamin E is beneficial for reducing melanoma risk. Details: A sub-group analysis of a large-scale clinical trial in patients with diabetes or cardiovascular disease suggests that taking RRR-alpha-tocopherol (natural vitamin E) 400 IU daily for about 7 years is not linked with a reduced risk of developing melanoma when compared with placebo (13036).
Menopausal symptoms. It is unclear if oral vitamin E is beneficial for reducing menopausal symptoms such as hot flashes. Details: A small clinical study in postmenopausal patients shows that taking vitamin E 200 IU twice daily for 8 weeks reduces hot flashes, but does not affect other menopausal symptoms or anxiety, when compared with placebo. The improvement in hot flashes was no longer present 4 weeks after the intervention (102969). However, a meta-analysis of 3 small clinical studies in postmenopausal patients, including the study above, shows that taking vitamin E 400 IU daily for 8 weeks does not reduce hot flash frequency when compared with placebo (111460).
Methotrexate toxicity. It is unclear if oral vitamin E reduces the risk of liver toxicity due to methotrexate. Details: An observational study in patients taking methotrexate for rheumatoid arthritis has found that taking vitamin E 400 mg twice daily for 3 months is associated with reductions in serum glutamic pyruvic transaminase (SGPT) and serum glutamic-oxaloacetic transaminase (SGOT) levels when compared with no supplementation. This suggests a reduction in liver injury in the treatment group (104414).
Muscular dystrophy. Small clinical studies suggest that oral vitamin E may not improve muscular dystrophy symptoms or progression. Details: Small clinical studies in patients with myotonic or Duchenne muscular dystrophy show that taking vitamin E along with penicillamine or selenium doesn't appear to slow disease progression or improve symptoms when compared with placebo (4703,4704).
Nocturnal leg cramps. It is unclear if oral vitamin E reduces leg cramps in veterans or in patients on hemodialysis. Details: A small clinical study in adults undergoing hemodialysis shows that taking vitamin E 400 IU at bedtime for 2 months seems to reduce the frequency of nocturnal leg cramps when compared with placebo (4701). However, another small clinical study in male veterans shows that taking vitamin E 800 IU at bedtime for 4 weeks does not reduce cramp frequency or severity or reduce sleep disturbances when compared with placebo (4702).
Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin E is beneficial in adults or children with NAFLD. Details: One meta-analysis of studies assessing both NAFLD patients and patients in whom NAFLD progressed to nonalcoholic steatohepatitis (NASH) shows that taking vitamin E 100-800 IU daily for 1-24 months improves liver enzyme levels, hepatic steatosis, and lobular inflammation when compared with control. However, taking vitamin E does not appear to improve hepatic fibrosis in these patients (97077). Methodological limitations such as publication bias and unclear calculations limit the reliability of these results. Another meta-analysis of 8 small clinical trials in adults with NAFLD shows that taking vitamin E 400-800 IU daily for up to 24 weeks improves liver enzyme levels when compared with placebo (112336). Vitamin E has also been evaluated in children with NAFLD. A meta-analysis of studies in this population shows that taking vitamin E 15-900 IU daily for up to 24 months reduces total and low-density lipoprotein (LDL) cholesterol levels, but does not affect liver enzyme levels, measures of insulin resistance, body mass index (BMI), ballooning degeneration of the liver, or liver fibrosis when compared with placebo (107861). Until additional data showing its benefit becomes available, practice guidelines by the American Association for the Study of Liver Diseases (AASLD) state that vitamin E is not recommended in patients with NAFLD without liver biopsy (98130).
Obesity. It is unclear if oral vitamin E is beneficial for improving weight loss. Details: A meta-analysis of 24 small clinical studies shows that taking oral vitamin E, 67-900 mg daily does not affect weight, body mass index (BMI), or waist circumference in adults with obesity. In fact, in people with a normal BMI, vitamin E seems to increase body weight (107859).
Oral mucositis. It is unclear if oral or topical vitamin E is beneficial in patients with oral mucositis from chemotherapy or radiotherapy. Details: Vitamin E has been evaluated in both chemotherapy- and radiation-induced mucositis. A small clinical study in children with chemotherapy-induced oral mucositis shows that a specific vitamin E product (Evion Paediatric Drops, Merck Limited) 200 IU applied topically in three divided doses daily for 1 week improves healing, pain, and the ability to eat when compared with placebo (94585). However, another small clinical study in patients receiving radiotherapy for head and neck cancer shows that taking vitamin E 1000 mg once daily with pentoxifylline 400 mg twice daily does not reduce the incidence or severity of oral mucositis and dysphagia when compared with control (102972).
Osteopenia. It is unclear if oral vitamin E helps slow the progression of osteopenia. Details: A small clinical study in postmenopausal adults with osteopenia who are taking calcium and vitamin D supplements shows that taking vitamin E (mixed tocopherols) 400 IU daily for 12 weeks prevents the increase in serum C-terminal telopeptide, a marker of bone resorption, seen with placebo over that same time period (107868).
Osteoporosis. It is unclear if oral vitamin E helps to reduce complications of osteoporosis such as fractures. Details: Observational research has found that vitamin E supplementation is associated with a 22% lower risk of hip fracture and a 14% lower risk of all fractures in elderly females with osteoporosis (90086). Additional observational research has found that higher dietary vitamin E intake is also associated with a 34% reduced risk of fractures in adults at risk for osteoporosis (104415).
Peyronie disease. It is unclear if oral vitamin E reduces Peyronie disease symptoms. Details: A small clinical study in patients with Peyronie disease shows that taking vitamin E 894 IU daily in addition to conservative treatment for 6 months does not improve pain, but may reduce plaque, when compared with using conservative treatment alone. Conservative treatment included verapamil 10 mg biweekly injection and iontophoresis, blueberries 160 mg orally daily, propolis 600 mg orally daily, and topical diclofenac 4% twice daily (90090). It is not clear if this effect is due to vitamin E, the other interventions, or the combination.
Photoreactive keratectomy. Oral vitamin E has only been evaluated for recovery after photoreactive keratectomy in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients undergoing laser surgery for myopia shows that taking vitamin A (retinol palmitate) 50,000-75,000 units with vitamin E (alpha-tocopheryl nicotinate) 343 IU daily seems to accelerate re-epithelialization, reduce haze formation, and improve visual acuity when compared with placebo (348).
Physical performance. It is unclear if oral vitamin E improves physical performance in the elderly. Details: Population research has found that increasing intake of dietary vitamin E is associated with increased physical performance and muscle strength in elderly people (14006).
Polycystic ovary syndrome (PCOS). Analyses of small clinical studies suggest that oral vitamin E may modestly reduce lipid levels in patients with PCOS. It is unclear if vitamin E can improve glycemic control, body weight, hormone levels, or symptoms of PCOS. Details: Meta-analyses of several small clinical studies in patients with PCOS show that taking vitamin E, alone or in combination with coenzyme Q10, fish oil, magnesium, or vitamin D, reduces total cholesterol by 9-18 mg/dL, low-density lipoprotein (LDL) cholesterol by 7-16 mg/dL, and triglycerides by 13-21 mg/dL when compared with placebo. However, vitamin E does not appear to increase high-density lipoprotein (HDL) cholesterol, reduce body weight, or improve hirsutism. The effects of vitamin E on glycemic indices and levels of testosterone, estradiol, and sex hormone binding globulin are unclear; individual meta-analyses show mixed results (112167,112168,112169). The validity of these findings is limited by a high degree of heterogeneity across the included studies, which varied in vitamin E dosing, treatment duration, and concomitant supplements used.
Premature rupture of membranes (PROM). Oral vitamin E does not seem to prevent PROM, although it's unclear if it might prevent premature delivery due to PROM. Details: Vitamin E has been evaluated for the prevention and management of PROM. A meta-analysis of clinical research shows that taking vitamin E with other ingredients throughout pregnancy does not affect the risk of developing PROM when compared with placebo (97075). However, a clinical study in patients with PROM shows that taking vitamin E (RRR-alpha-tocopherol acetate) 400 IU and vitamin C 1000 mg daily, starting within 1 hour of membrane rupture and continuing for an unspecified amount of time, seems to hold back premature delivery by about 5 days when compared with placebo. However, maternal or neonatal outcomes did not seem to be affected (90078). It is not clear if this effect is due to vitamin E, vitamin C, or the combination.
Radiation-induced sialadenitis. It is unclear if oral vitamin E is effective for the prevention or treatment of radiation-induced sialadenitis. Details: A small clinical study in patients undergoing radiation therapy for thyroid cancer shows that taking vitamin E 200 mg daily for 5 weeks, starting 1 week before radiotherapy, improves several measures of parotid and submandibular salivary gland function when compared to baseline, suggesting that vitamin E might prevent radiation-induced sialadenitis and its associated complications (112332). The validity of these findings is limited by a lack of control group.
Radiation dermatitis. It is unclear if topical vitamin E is effective for the prevention or treatment of radiation dermatitis. Details: A small clinical study in patients undergoing radiation therapy for breast cancer shows that applying a cream containing nanoparticles of vitamin E 2%, three times daily and after each radiation session until 2 weeks after radiation therapy is complete, does not reduce the severity of radiation dermatitis or improve quality of life when compared with a placebo cream. However, in patients that did not receive a boosted radiation dose, this vitamin E cream seems to slightly delay the onset of dermatitis when compared with placebo (112333).
Radiation fibrosis. It is unclear if topical vitamin E reduces radiation fibrosis symptoms. Details: Clinical research shows that taking vitamin E 1000 IU orally with pentoxifylline 800 mg daily seems to reverse radiation fibrosis (4672,4673). Regression of radiation fibrosis becomes significant after three months of treatment and continues to improve thereafter. After 12 months of treatment, mean surface area of fibrosis can decrease by 66% (4672). It is unclear if the benefit is due to vitamin E, pentoxifylline, or the combination. One very small study suggests that vitamin E alone does not seem to be effective when compared with placebo (10363).
Renal cell carcinoma. It is unclear if oral vitamin E reduces renal cell carcinoma risk. Details: In 2009, the US Food and Drug Administration (FDA) approved a qualified health claim regarding vitamin E and renal cell carcinoma risk. This qualified health claim was based on one weak and limited study. The FDA has determined that it is highly uncertain that vitamin E supplements reduce the risk of renal cell carcinoma (102332).
Restless legs syndrome (RLS). Oral vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in hemodialysis patients shows that taking vitamin E 596 IU, vitamin C 200 mg, or a combination of both daily for 8 weeks modestly reduces severity of restless legs syndrome when compared with placebo (90093).
Retinopathy of prematurity. It is unclear whether oral or parenteral vitamin E reduces the risk for retinopathy in prematurity (ROP). Details: A clinical study in very low birth weight infants with respiratory distress syndrome suggests that giving vitamin E 12.5 IU twice daily from 72 hours after birth through 28 days of age might reduce the incidence of stage 1 ROP when compared with placebo. However, the difference reached significance in the per-protocol analysis, but not in the intention-to-treat analysis (107864). Also, a meta-analysis that did not include this more recent study shows that administering oral, intravenous, or intramuscular vitamin E daily does not reduce the risk for ROP. Additionally, high levels of vitamin E and large intravenous doses of vitamin E have been associated with an increased risk for sepsis in premature infants (85062).
Rheumatoid arthritis (RA). It is unclear if oral vitamin E is beneficial in patients with RA. Details: A small clinical study in adults with RA shows that taking vitamin E 600 mg twice daily in conjunction with standard therapy for 12 weeks is superior to standard therapy alone for reducing pain, but not inflammation (4723). However, other studies show mixed results. A meta-analysis of 7 small clinical studies in patients with RA shows that taking vitamin E up to 1200 IU daily for up to 12 weeks does not reduce pain, tenderness, swelling, or morning stiffness when compared with control (112330).
Schizophrenia. Oral vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking vitamin E (RRR-alpha-tocopherol) 135.8 IU and a specific ascorbic acid supplement (CellaVie) 250 mg with or without ethyl eicosapentaenoate 500 mg daily for 16 weeks does not improve negative or positive symptoms of schizophrenia when compared with placebo (89234).
Sickle cell disease. Although there is interest in using oral vitamin E for sickle cell disease, there is insufficient reliable information about the clinical effects of vitamin E for this condition.
Stretch marks (striae gravidarum). Topical vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that using a moisturizer containing vitamin E, rosehip oil, hydroxyprolisilane C, and gotu kola triterpenes at least twice daily on affected areas does not decrease incidence of new stretch marks, but does decrease the severity of new stretch marks by about 30%, when compared with control cream in pregnant patients (90076). It is not clear if this effect is due to vitamin E, other ingredients, or the combination.
Stroke. It is unclear if oral vitamin E is beneficial for reducing stroke risk. Details: A trial-sequential meta-analysis of 12 clinical trials with 148,000 patients shows that vitamin E does not seem to reduce the risk of total stroke when compared with placebo. However, in a subgroup analysis, vitamin E was associated with an 8% lower risk of ischemic stroke and a trend to an increased risk of hemorrhagic stroke when compared with placebo. Based on subgroup analyses, there was no difference on risk based on vitamin E dosage, use of synthetic versus natural vitamin E, and whether prevention was primary or secondary (104408). This analysis was limited due to high heterogeneity, small study size, and insufficient power to detect differences between treatments. Older meta-analyses also found mixed results of using vitamin E 74.5-1192 IU daily alone or in combination for up to 10 years. However, there was a similar sub-group analysis finding that vitamin E might reduce the risk of ischemic stroke, but it might also increase the risk of hemorrhagic stroke (14621,85201). Some clinical research shows that taking all-rac-alpha-tocopherol (synthetic vitamin E) might reduce the risk of ischemic stroke in male smokers with hypertension and diabetes (3359).
Sunburn. Topical vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Oral vitamin E alone does not seem to prevent sunburn. Details: Two small, double-blind, placebo-controlled studies suggest that taking high dose oral RRR-alpha-tocopherol (natural vitamin E) up to 2 grams daily in combination with vitamin C 3 grams protects against skin inflammation after exposure to ultraviolet (UV) radiation. However, taking vitamin E alone does not seem to be beneficial when compared with control (4715,4716). This combination was also tried topically. In one study, topically applied vitamin E in combination with topical vitamin C and melatonin provided modest photoprotective effect when used prior to UV exposure, but had no effect when used during or after UV exposure (4713,4714).
Uveitis. Oral vitamin E has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking vitamin E 149 IU twice daily with vitamin C 500 mg daily for 8 weeks improves visual acuity in patients with acute anterior uveitis, but does not seem to decrease inflammation measured by laser flare, when compared with placebo (4730). It is not clear if this effect is due to vitamin E, vitamin C, or the combination.
Vaginal atrophy. It is unclear if a vitamin E suppository is beneficial in patients with vaginal atrophy. Details: A small clinical study in females with breast cancer and tamoxifen-induced vaginal atrophy shows that intravaginal administration of a vitamin E 1 mg suppository nightly before bed for 8 weeks improves self-reported symptoms of vaginal atrophy, decreases vaginal pH, and improves vaginal estrogenization, as measured by the Vaginal Maturation Index, when compared with placebo (99773). More evidence is needed to rate vitamin E for these uses.

WHEATGRASS (organic Wheat Grass fine ground powder)

Beta-thalassemia. One small, low-quality study suggests that drinking wheatgrass juice 100 mL daily for 18 months can reduce blood transfusion requirements in some children with beta-thalassemia major when compared to baseline (85601). A small clinical study in children with beta-thalassemia major shows that taking wheatgrass tablets in doses of 1-1.5 grams daily for children aged 1-3 years, 3 grams daily for children 4-8 years, and 4 grams daily for children aged 9 years and older for 12 months decreases the mean blood transfused as packed cells by about 18%, increases mean hemoglobin by about 7%, and increases the mean interval between consecutive blood transfusions by about 5 days when compared to baseline (93021). However, these studies have been criticized for methodological problems, including high dropout rates ranging from to 18% to 58%. Another small clinical study shows that taking wheat grass tablets 100 mg/kg daily for 6 months followed by 200 mg/kg daily for an additional 6 months does not reduce the transfusion requirement in children or adults with beta-thalassemia major (93020).
Hypercholesterolemia. Preliminary clinical research shows that taking freeze-dried wheatgrass powder 3.5 grams daily for 10 weeks reduces total cholesterol by 5% and triglycerides by 10% when compared to baseline in females aged 30-60 years with elevated cholesterol levels. However, taking wheatgrass powder does not reduce low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or fasting blood glucose levels in these patients (95906).
Plantar heel pain. Preliminary clinical research shows that applying a wheatgrass 10% cream topically to the bottom of the feet twice daily for 6 weeks is no more effective than placebo for reducing pain or improving measures of injury resolution (85602).
Ulcerative colitis. A small clinical study in adults with active distal ulcerative colitis shows that drinking 100 mL of freshly extracted wheatgrass juice daily for 1 month might modestly reduce overall disease activity and the severity of rectal bleeding when compared with placebo (11165). More evidence is needed to rate the effectiveness of wheatgrass for these uses.

Safety view details

Below is general information about the safety of the known ingredients contained in the product Daily Veggie. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

BARLEY (organic Barley Grass fine ground powder)

LIKELY SAFE ...when used orally and appropriately in food amounts (4819,4820,4821,5104,10166,10435,11134,11463,11986,92818). There is insufficient reliable information available about the safety of barley when used orally in medicinal amounts or when applied topically.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods (19).

PREGNANCY: POSSIBLY UNSAFE
when barley sprouts are consumed in relatively high doses. Excessive amounts of barley sprouts should not be consumed during pregnancy (19).

LACTATION:
Insufficient reliable information available; avoid using.

LIKELY SAFE ...when used in amounts commonly found in foods.

POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes, short term. Beetroot juice has been safely used in clinical trials in doses of up to 500 mL daily for up to 7 days and a beetroot-based nutritional gel has been used safely in doses of up to 100 grams daily for 8 days (94461,94462,94464,100149,100152,100153).

PREGNANCY AND LACTATION:
There is insufficient reliable information available about the safety of beets used medicinally during pregnancy and breast-feeding.

POSSIBLY SAFE ...when non-contaminated species of spirulina blue-green algae are used orally and appropriately (91713). The blue-green algae species Arthrospira platensis has been used with apparent safety in doses up to 19 grams daily for 2 months, or 10 grams daily for 6 months (18296,18300,18306,75944,91705,99703,104567,109965). The blue-green algae species Arthrospira fusiformis has been used with apparent safety in doses up to 4 grams daily for 3 months, or 1 gram daily for 12 months (15782,91717). Another blue-green algae species, Arthrospira maxima, has been used with apparent safety in a dose of 4.5 grams daily for up to 12 weeks (18297,99654,99655,102688). ...when non-contaminated, non-toxin producing strains of blue-green algae from the Aphanizomenon flos-aquae species are used orally and appropriately. Doses up to 1.6 grams daily have been used with apparent safety for up to 6 months (14842,18310). Some blue-green algae species can produce toxins called microcystins. According to the World Health Organization (WHO), the tolerable daily intake of microcystins in adults is 0.04 mcg/kg (96549).

POSSIBLY UNSAFE ...when contaminated blue-green algae are used orally. Blue-green algae can be contaminated with heavy metals (including mercury, cadmium, lead, or arsenic), neurotoxins, and toxic microcystin-producing cyanobacteria such as Microcystis aeruginosa (9171,75966,91704,91711,96550). Microcystins are most commonly reported in the blue-green algae species Aphanizomenon flos-aquae harvested from Upper Klamath Lake in Oregon. The Oregon Department of Health has set a limit of 1 mcg of microcystin-LR equivalents per gram dry weight of blue-green algae, assuming consumption of about 2 grams/day by adults (91704,91713). However, many samples of Aphanizomenon flos-aquae have been reported to contain higher levels than this (9171,91704). According to the World Health Organization (WHO), the tolerable daily intake of microcystins in adults is 0.04 mcg/kg (96549). When consumed orally, microcystins accumulate in the liver, binding to and inhibiting protein phosphatases, causing hepatocyte damage and possible tumor promotion (9171). Aphanizomenon flos-aquae can also produce neurotoxic compounds that may be present in supplements containing this organism (91704).

CHILDREN: POSSIBLY UNSAFE
when blue-green algae products are used orally. Blue-green algae can accumulate heavy metals such as lead and mercury (91704,91711). They can also contain toxic microcystins produced by contaminating species of cyanobacteria such a Microcystis aeruginosa (91704). Children are more sensitive to poisoning by microcystins (3536). The Oregon Department of Health has set a limit for microcystins of 1 mcg per gram dry weight of blue-green algae, but some countries have set very low exposure limits of 0.2 mcg per day and 0.8 mcg per day for infants and children, respectively (91704).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using. Some blue-green algae products, specifically those of the species Aphanizomenon flos-aquae, have been found to contain low amounts of beta-methylamino-L-alanine (BMAA). BMAA is associated with neurodegenerative diseases, and breast milk has been shown to be a potential source of BMAA exposure in infants (96550).

LIKELY SAFE ...when used orally in food amounts (14145). There is insufficient reliable information available about the safety of broccoli when used in medicinal amounts.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in food amounts (14145). There is insufficient reliable information available about the safety of broccoli when used in medicinal amounts during pregnancy and lactation; avoid using.

BRUSSELS SPROUT (organic Brussels Sprouts powder)

LIKELY SAFE ...when used in amounts commonly found in foods. There is insufficient reliable information available about the safety of Brussels sprout when used in medicinal amounts.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid amounts in excess of those found in foods.

LIKELY SAFE ...when used orally in amounts commonly found in foods.

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts (18). ...when used topically and appropriately, short-term. Topical application of cabbage leaves has been general well-tolerated in short-term studies (6781,6782,6783,6784,93671,110558). However, pain, itching, and burning with topical use of cabbage leaves have been reported in some patients leaving cabbage leaf wraps in place for 2-4 hours (93671,93675).

PREGNANCY:
There is insufficient reliable information available about using cabbage in medicinal amounts during pregnancy; avoid using.

LACTATION: LIKELY SAFE
when used topically and appropriately, short-term. Significant adverse effects have not been reported in short-term studies (6781,6782,6783,6784,93673,93677). There is insufficient reliable information available about using cabbage orally in medicinal amounts during lactation; avoid using.

LIKELY SAFE ...when used orally in amounts commonly found in foods. Carrot essential oil, extracts, and food additives have Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally in medicinal amounts, short-term. Carrot has been used safely in doses of approximately 100 grams three times daily for up to 4 weeks (96308). There is insufficient reliable information available about the safety of carrot when used topically.

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in foods (4912). Carrot essential oil, extracts, and food additives have Generally Recognized as Safe (GRAS) status in the US (4912).

CHILDREN: POSSIBLY UNSAFE
when carrot juices are used excessively in nursing bottles for small children. Excessive use of carrot juice may cause carotenemia and dental caries (25817).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in food (4912). Carrot essential oil, extracts, and food additives have Generally Recognized as Safe (GRAS) status in the US (4912). There is insufficient reliable information available about the safety of carrot when used in medicinal amounts during pregnancy and lactation.

LIKELY SAFE ...when celery stems are consumed as food. ...when celery oil or seeds are consumed in amounts commonly found in foods. Celery seed has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when celery seed is used orally and appropriately in medicinal amounts, short-term (12). Celery seed powder has been safely used at doses up to 1500 mg daily for up to 6 weeks and 750 mg daily for up to 12 weeks. Celery seed extract has been safely used at doses up to 1340 mg daily for up to 4 weeks (106486,110755,112409,112411). ...when celery seed extract is used topically and appropriately, short-term (40988,41049,41052).

PREGNANCY: LIKELY UNSAFE
when celery oil or seeds are used orally in larger amounts; celery might have uterine stimulant or abortifacient effects (4,19,19104).

LACTATION:
There is insufficient reliable information available about the safety of medicinal amounts of celery during lactation; avoid using.

LIKELY SAFE ...when used in amounts commonly found in foods. There is insufficient reliable information available about the safety of collard when used orally in medicinal amounts.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid amounts in excess of those found in foods.

FOLIC ACID

LIKELY SAFE ...when used orally or parenterally and appropriately. Folic acid has been safely used in amounts below the tolerable upper intake level (UL). The UL for folic acid is based only on supplemental folic acid and is expressed in mcg folic acid. Dietary folate is not included in UL calculations, as dietary folate consumption has not been associated with adverse effects. The UL for folic acid in adults is 1000 mcg (6241). In cases of megaloblastic anemia resulting from folate deficiency or malabsorption disorders such as sprue, oral doses of 1-5 mg per day can also be used safely until hematologic recovery is documented, as long as vitamin B12 levels are routinely measured (6241,7725,8739).

POSSIBLY SAFE ...when L-5-methyltetrahydrofolate (L-5-MTHF), the reduced form of folate, is used orally and appropriately, short-term. L-5-MTHF has been used with apparent safety at a dose of 416 mcg daily for 16 weeks (104913,104914) and a dose of 113 mcg daily for 24 weeks (104920). A specific L-5-MTHF product (Metafolin, Eprova) has been used with apparent safety at a dose of 1.3 mg daily for 12 weeks (104912).

POSSIBLY UNSAFE ...when used orally in large doses, long-term. Clinical research shows that taking folic acid daily in doses of 800 mcg to 1200 mcg for 3-10 years significantly increases the risk of developing cancer and adverse cardiovascular effects compared to placebo (12150,13482,16822,17041). Doses above 1 mg per day should also be avoided if possible to prevent precipitation or exacerbation of neuropathy related to vitamin B12 deficiency (6241,6242,6245). However, there is contradictory evidence suggesting that higher doses may not be harmful. There is some evidence that doses of 5 mg per day orally for up to 4 months can be used safely if vitamin B12 levels are routinely measured (7725). Also, other clinical research suggests that folic acid supplementation at doses up to 5 mg, usually in combination with vitamin B12, does not increase the risk of cancer when taken for 2-7 years (91312). Very high doses of 15 mg per day can cause significant central nervous system (CNS) and gastrointestinal side effects (505).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Folic acid has been safely used in children in amounts below the tolerable upper intake level (UL). The ULs for folic acid are based only on supplemental folic acid and are expressed in mcg folic acid. Dietary folate is not included in UL calculations, as dietary folate consumption has not been associated with adverse effects. The UL for children is: 1-3 years of age, 300 mcg; 4-8 years of age, 400 mcg; 9-13 years of age, 600 mcg; 14-18 years of age, 800 mcg (6241).

CHILDREN: POSSIBLY SAFE
when L-5-methyltetrahydrofolate (L-5-MTHF), the reduced form of folate, is used orally and appropriately. One clinical study in infants aged 27 days and younger shows that consuming a formula containing L-5-MTHF (Metafolin, Merck & Cie) 10.4 mcg/100 mL daily has been used with apparent safety for up to 12 weeks (104918).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Folic acid 300-400 mcg is commonly used during pregnancy for prevention of neural tube defects (8739). Miscarriage rates and negative impacts on fetal growth have not been shown to increase with peri-conception supplemental folic acid intakes of 4 mg per day (91320,91322). However, other research shows that taking more than 5 mg per day during pregnancy may reduce development of cognitive, emotional, and motor skills in infants (91318). Also, the tolerable upper intake level (UL) of folic acid for pregnant or lactating women is 800 mcg daily for those 14-18 years of age and 1000 mcg daily for those 19 years and older (6241).

PREGNANCY AND LACTATION: POSSIBLY SAFE
when L-5-methyltetrahydrofolate (L-5-MTHF), the reduced form of folate, is used orally and appropriately, short-term. L-5-MTHF has been used with apparent safety at a dose of 416 mcg daily for 16 weeks during lactation. Compared to folic acid, this form seems to further increase the folate concentration of red blood cells, but not breast milk (104913,104914).

POSSIBLY SAFE ...when applied topically to the skin. A gel containing 1% Fucus vesiculosus extract, applied to the skin twice daily, has been used in clinical research with apparent safety for up to 5 weeks (12799).

POSSIBLY UNSAFE ...when used orally due to its iodine content and possible heavy metal content. Fucus vesiculosus contains up to 0.05% iodine or 226 mcg/gram dry weight (12789,74217). Ingesting more than 150 mcg of iodine daily can cause hyperthyroidism or exacerbate existing hyperthyroidism (12788). Fucus vesiculosus can also contain heavy metals, including cadmium, arsenic, and lead, and can cause heavy metal nephropathy (12789,12800,74213).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally because it may contain iodine and heavy metals (12789,74213,74217); avoid using.

LIKELY SAFE ...when used orally and appropriately. Garlic has been used safely in clinical studies lasting up to 7 years without reports of significant toxicity (1873,4782,4783,4784,4785,4786,4787,4789,4790,4797)(4798,6457,6897,14447,96008,96009,96014,102016,102670,103479)(107238,107239,107352,108607,110722,111763).

POSSIBLY SAFE ...when used topically. Garlic-containing gels, lipid-soluble garlic extracts, garlic pastes, and garlic mouthwashes have been safely used in clinical research for up to 3 months (4766,4767,8019,15030,51330,51386). ...when used intravaginally. A vaginal cream containing garlic and thyme has been safely used nightly for 7 nights (88387).

POSSIBLY UNSAFE ...when raw garlic is used topically (585). Raw garlic might cause severe skin irritation when applied topically.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods (3319).

PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts. Garlic is reported to have abortifacient activity (11020). One study also suggests that garlic constituents are distributed to the amniotic fluid after a single dose of garlic (4828). However, there are no published reports of garlic adversely affecting pregnancy. In clinical research, garlic 800 mg daily was used during the third trimester of pregnancy with no reported adverse outcomes (9201,51626). There is insufficient reliable information available about the safety of topical garlic during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (3319).

LACTATION: POSSIBLY UNSAFE
when used orally in amounts greater than those found in foods. Several small studies suggest that garlic constituents are secreted in breast milk, and that nursing infants of mothers consuming garlic are prone to extended nursing (3319,4829,4830). There is insufficient reliable information available about the safety of topical garlic during lactation.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately for up to 8 weeks. Garlic extract 300 mg three times daily has been used with apparent safety for up 8 weeks in children ages 8-18 years (4796). There is insufficient reliable information available about the safety of garlic when used over longer durations or in higher doses.

CHILDREN: POSSIBLY UNSAFE
when raw garlic is used topically. Raw garlic might cause severe skin irritation when applied topically (585,51210).

LIKELY SAFE ...when the root is used orally in amounts commonly found in foods. Horseradish has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts (2,4,6,12,18). Horseradish has been used with apparent safety at a dose of 480 mg daily for 12 weeks (96309). ...when topical preparations containing no more than 2% mustard oil, a constituent of horseradish, are used (2).

CHILDREN: LIKELY UNSAFE
when used orally in children less than 4 years of age because it can cause gastrointestinal problems (2,12,19). PREGNANCY AND:

CHILDREN: LIKELY SAFE
when the root is used orally in amounts commonly found in foods. Horseradish has Generally Recognized as Safe (GRAS) status in the US (4912).

CHILDREN: LIKELY UNSAFE
when the tincture is used regularly and in large amounts, as it is considered an abortifacient (19).

LACTATION: LIKELY SAFE
when the root is used orally in amounts commonly found in foods. Horseradish has Generally Recognized as Safe (GRAS) status in the US (4912).

LACTATION: LIKELY UNSAFE
when used orally in large amounts. The mustard oils produced by glucosinolates from horseradish are considered toxins that can be excreted through breast milk (33031).

LIKELY SAFE ...when used in amounts commonly found in foods. There is insufficient reliable information available about the safety of kale when used orally in medicinal amounts.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. There is insufficient reliable information available about the safety of kale when used orally in medicinal amounts; avoid use.

LIKELY SAFE ...when used in amounts found in foods. Laminaria has Generally Recognized as Safe (GRAS) status in the US (94048).

POSSIBLY SAFE ...when iodine-reduced laminaria supplements are used, short-term. Iodine-reduced laminaria powder has been safely used at doses up to 6 grams daily for up to 8 weeks (109572).

POSSIBLY UNSAFE ...when used orally in medicinal amounts. The average laminaria-based supplement might contain as much as 1000 mcg of iodine. Ingesting more than 1100 mcg iodine daily (the tolerable upper intake level) can cause hypothyroidism, hyperthyroidism, or exacerbate existing hyperthyroidism (9556,94046). In addition, some laminaria supplements may contain arsenic (645,10275,15588). There is insufficient reliable information available about the safety of laminaria for its other uses.

PREGNANCY: POSSIBLY UNSAFE
when used intravaginally for cervical ripening; there is an increased risk of parental and neonatal infection (8945).

PREGNANCY: LIKELY UNSAFE
when used intravaginally to induce labor; use has been associated with endometriosis, neonatal sepsis, fetal hypoxia, and intrauterine death (6).

PREGNANCY: UNSAFE
when used orally due to potential hormonal effects (19); avoid using.

LACTATION: LIKELY UNSAFE
when used orally because of potential toxicity (19).

LIPASE

There is insufficient reliable information available about the safety of lipase.

CHILDREN: POSSIBLY UNSAFE
when recombinant human bile salt-stimulated lipase (rhBSSL) is used orally by premature infants. Adding rhBSSL to infant formula or pasteurized breast milk increases the risk for serious gastrointestinal adverse effects in premature infants (101940).

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

LIKELY SAFE ...when used orally and appropriately in food amounts (4960,4969,5792,5797). Oat bran has Generally Recognized as Safe (GRAS) status in the US (4912). Whole grain oats 50-100 grams daily have been used for up to 1 year without serious adverse effects (97520).

POSSIBLY SAFE ...when used topically and appropriately (12). Lotion containing colloidal oat 1% has been used topically without adverse effects for up to 6 weeks (97518,103340). There is insufficient reliable information available about the safety of oats when used orally in medicinal amounts.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in food amounts (5792,5797).

LIKELY SAFE ...when consumed in amounts commonly found in foods. Onion has Generally Recognized as Safe (GRAS) status in the US (4912). ...when onion extract is used topically (66742,66883,66895,66903,67089,95151,95154,95156).

POSSIBLY SAFE ...when onion extract is used orally and appropriately (2). Onion extract has been used safely in doses of 300 mg three times daily for up to 12 weeks (95149,101747).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using in amounts greater than used in foods.

LIKELY SAFE ...when used orally in amounts commonly found in foods. Parsley has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, short-term (12,13173).

LIKELY UNSAFE ...when used orally in very large doses e., 200 grams). Parsley oil contains significant amounts of the potentially toxic constituents, apiole and myristicin (11). Apiole can cause blood dyscrasias, kidney toxicity, and liver toxicity; myristicin can cause giddiness and hallucinations (4). ...when parsley seed oil is used topically. Applying parsley seed oil to the skin can cause photodermatitis upon sun exposure (4). There is insufficient reliable information available about the safety of the topical use of parsley leaf and root.

PREGNANCY: LIKELY UNSAFE
when used orally in medicinal amounts. Parsley has been used orally as an abortifacient and to stimulate menstrual flow (4,12,515,19104,92873). Population evidence suggests that maternal intake of An-Tai-Yin, an herbal combination product containing parsley and dong quai, during the first trimester increases the risk of congenital malformations of the musculoskeletal system, connective tissue, and eyes (15129).

LACTATION:
Insufficient reliable information available; avoid using.

PHYTASE

LIKELY SAFE ...when consumed in the amounts commonly found in foods. There is insufficient reliable information available about the safety of phytase when used orally as a supplement.

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

POSSIBLY SAFE ...when used orally and appropriately. Various proteolytic enzymes have been safely used orally in clinical research (716,964,965,968,969,6252,6253,10622,11457,18281,18284) (91104,91105,91106,91111,96449). Side effects are typically mild to moderate and most often include gastrointestinal effects. See specific monographs for more detailed information related to the safety of individual proteolytic enzymes. ...when used topically and appropriately. Various proteolytic enzymes have been safely used topically in clinical research (67835,67843,67845,91113). Some proteolytic enzymes might cause allergic reactions when used topically. See specific monographs for more detailed information related to the safety of individual proteolytic enzymes.

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

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

POSSIBLY SAFE ...when the seed or seed oil is used orally and appropriately in medicinal amounts, short-term. Pumpkin seed has been used with apparent safety in a dose of up to 10 grams daily for up to 12 months (92383). Pumpkin seed oil has been used with apparent safety in a dose of up to 400 mg daily for up to 6 months (92378). There is insufficient reliable information available about the safety of pumpkin seed oil when used topically.

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

LIKELY SAFE ...when used orally and appropriately. Selenium appears to be safe when taken short-term in amounts below the tolerable upper intake level (UL) of 400 mcg daily (4844,7830,7831,7836,7841,9724,9797,14447,17510,17511)(17512,17513,17515,17516,97087,97943,109085); however, there is concern that taking selenium long-term might not be safe. Some evidence shows that consuming a diet containing more than the recommended dietary allowance (RDA) of selenium, which is 55 mcg daily for most adults, is associated with an increased risk for developing type 2 diabetes (99661). Some evidence also shows that taking a selenium supplement 200 mcg daily for an average of 3-8 years increases the risk of developing type 2 diabetes (97091,99661). Higher serum levels of selenium are also associated with an increased risk of developing diabetes and increased mortality (16710,99661). ...when used intravenously. Selenium, as selenious acid, is an FDA-approved drug. Sodium selenite intravenous infusions up to 1000 mcg daily have been safely used for up to 28 days (90347,92910).

POSSIBLY UNSAFE ...when used orally in high doses or long-term. Doses above 400 mcg daily can increase the risk of developing selenium toxicity (4844,7825). Additionally, some evidence shows that consuming a diet containing more than the recommended dietary allowance (RDA) of selenium, which is 55 mcg daily for most adults, is associated with an increased risk for developing type 2 diabetes (99661). There is also concern that taking a selenium supplement 200 mcg daily long-term, for an average of 3-8 years, increases the risk of developing type 2 diabetes (99661). Higher serum levels of selenium are also associated with an increased risk of developing diabetes and increased mortality (16710,99661).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. Selenium seems to be safe when used short-term in doses below the tolerable upper intake level (UL) of 45 mcg daily for infants up to age 6 months, 60 mcg daily for infants 7 to 12 months, 40-90 mcg daily for children 1 to 3 years, 100-150 mcg daily for children 4 to 8 years, 200-280 mcg daily for children 9 to 13 years, and 400 mcg daily for children age 14 years and older (4844,86095); however, there is some concern that long-term use might not be safe. ...when used via a nasogastric tube in premature infants (7835,9764).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately. Selenium appears to be safe when used short-term in amounts that do not exceed the tolerable upper intake level (UL) of 400 mcg daily (4844,17507,74419,74481,74391); however, there is concern that long-term use might not be safe.

PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive doses. Doses above 400 mcg daily may cause significant toxicity (4844).

LACTATION: POSSIBLY SAFE
when used orally and appropriately. Selenium appears to be safe when used short-term in amounts that do not exceed the tolerable upper intake level (UL) of 400 mcg daily when taken short-term (4844,74467); however, there is concern that long-term use might not be safe.

LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. Doses above 400 mcg daily may cause significant toxicity (4844,7838). ...when used orally in HIV-positive women. Selenium supplementation in HIV-positive women not taking highly active antiretroviral therapy may increase HIV-1 levels in breast milk (90358).

LIKELY SAFE ...when used in amounts commonly found in foods.

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Spinach has been used with apparent safety at a dose of 5 grams daily for up to 12 weeks (96856).

CHILDREN: LIKELY SAFE
when consumed in the amounts commonly found in foods by children older than 4 months of age (18).

CHILDREN: LIKELY UNSAFE
when used orally in infants under 4 months old; the high nitrate content of spinach can cause methemoglobinemia (18). There is insufficient reliable information available about the safety of spinach in children when used in medicinal amounts.

PREGNANCY AND LACTATION: LIKELY SAFE
when used in amounts commonly found in foods; avoid medicinal amounts.

LIKELY SAFE ...when the ripe or unripe tomato fruit or its products are consumed in amounts found in foods (2406,9439,10418,106653,106654). ...when tomato leaf is consumed in regular food amounts (18).

POSSIBLY SAFE ...when a tomato extract is used orally for medicinal purposes. A specific tomato extract (Lyc-O-Mato, LycoRed Ltd) has been used with apparent safety in clinical studies lasting up to 8 weeks (7898,14287,102182).

POSSIBLY UNSAFE ...when the tomato leaf or unripe green tomato fruit is used orally in excessive amounts. Tomato leaf and unripe green tomatoes contain tomatine, which has been associated with toxicity when consumed in large quantities (18,102957). There is insufficient reliable information available about the safety of the tomato vine.

PREGNANCY AND LACTATION: LIKELY SAFE
when the tomato fruit or its products are consumed in typical food amounts. There is insufficient reliable information available about the safety of tomato extracts when used during pregnancy or lactation; avoid using.

VITAMIN A

LIKELY SAFE ...when used orally or intramuscularly and appropriately. Vitamin A, as pre-formed vitamin A (retinol or retinyl ester), is safe in adults when taken in doses below the tolerable upper intake level (UL) of 10,000 IU (3000 mcg) per day (7135). Higher doses increase the risk of side effects. There is also growing concern that taking high doses of antioxidants such as vitamin A might do more harm than good. In an analysis of studies, taking vitamin A supplements alone or in combination with other antioxidants is associated with an increased risk of mortality from all causes (15305,90775). Keep in mind that vitamin A is available in two different forms: pre-formed vitamin A (retinol or retinyl ester) and provitamin A (carotenoids). The safety concerns associated with high vitamin A intake occur with pre-formed vitamin A only. Some supplements contain vitamin A in both pre-formed and provitamin A forms. For these supplements, the amount of pre-formed vitamin A should be used to determine if the amount of vitamin A is safe.

POSSIBLY SAFE ...when used topically and appropriately, short-term. Retinol 0.5% has been used on the skin daily for up to 12 weeks with apparent safety. No serious adverse effects have been reported in clinical trials (103671,103680).

POSSIBLY UNSAFE ...when used orally in high doses. Doses higher than the UL of 10,000 IU (3000 mcg) per day of pre-formed vitamin A (retinol or retinyl ester) might increase the risk of side effects (7135). While vitamin A 25,000 IU (as retinyl palmitate) daily for 6 months followed by 10,000 IU daily for 6 months has been used with apparent safety in one clinical trial (95052), prolonged use of excessive doses of vitamin A can cause significant side effects such as hypervitaminosis A. The risk for developing hypervitaminosis A is related to total cumulative dose of vitamin A rather than a specific daily dose (1467,1469). There is also concern that taking high doses of antioxidants such as vitamin A might do more harm than good. In an analysis of studies, taking vitamin A supplements alone or in combination with other antioxidants is associated with an increased risk of mortality from all causes (15305,90775). There is insufficient reliable information available about the safety of using sublingual formulations of vitamin A.

CHILDREN: LIKELY SAFE
when used orally or intramuscularly and appropriately. The amount of pre-formed vitamin A (retinol or retinyl ester) that is safe depends on age. For children up to 3 years of age, doses less than 2000 IU (600 mcg) per day seem to be safe. For children ages 4 to 8, doses less than 3000 IU (900 mcg) per day seem to be safe. For children ages 9 to 13, doses less than 5667 IU (1700 mcg) per day seem to be safe. For children 14 to 18, doses less than 9333 IU (2800 mcg) per day seem to be safe (7135). Keep in mind that vitamin A is available in two different forms: pre-formed vitamin A (retinol or retinyl ester) and provitamin A (carotenoids). The safety concerns associated with high vitamin A intake occur with pre-formed vitamin A only. Some supplements contain vitamin A in both pre-formed and provitamin A forms. For these supplements, the amount of pre-formed vitamin A should be used to determine if the amount of vitamin A is safe.

CHILDREN: POSSIBLY UNSAFE
when pre-formed vitamin A (retinol or retinyl ester) is used orally in excessive doses. For children up to 3 years of age, avoid doses greater than 2000 IU (600 mcg) per day. For children ages 4 to 8, avoid doses greater than 3000 IU (900 mcg) per day. For children ages 9 to 13, avoid doses greater than 5667 IU (1700 mcg) per day. For children ages 14 to 18, avoid doses greater than 9333 IU (2800 mcg) per day (7135). Higher doses of vitamin A supplementation have been associated with increased risk of side effects such as pneumonia, bone pain, and diarrhea (319,95051). Long-term supplementation with low to moderate doses on a regular basis can cause severe, but usually reversible, liver damage (11978).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally or intramuscularly and appropriately. Vitamin A, as pre-formed vitamin A (retinol or retinyl ester), is safe during pregnancy and lactation when used in doses less than 10,000 IU (3000 mcg) per day (7135,16823,107293). Keep in mind that vitamin A is available in two different forms: pre-formed vitamin A (retinol or retinyl ester) and provitamin A (carotenoids). The safety concerns associated with high vitamin A intake occur with pre-formed vitamin A only. Some supplements contain vitamin A in both pre-formed and provitamin A forms. For these supplements, the amount of pre-formed vitamin A should be used to determine if the amount of vitamin A is safe.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally or intramuscularly in excessive doses. Daily intake of greater than 10,000 IU (3000 mcg) can cause fetal malformations (3066,7135). Excessive dietary intake of vitamin A has also been associated with teratogenicity (11978). The first trimester of pregnancy seems to be the critical period for susceptibility to vitamin A-associated birth defects such as craniofacial abnormalities and abnormalities of the central nervous system (7135). Pregnant patients should monitor their intake of pre-formed vitamin A (retinol or retinyl ester). This form of vitamin A is found in several foods including animal products, some fortified breakfast cereals, and dietary supplements (3066).

VITAMIN E

LIKELY SAFE ...when used orally or topically and appropriately. Vitamin E is generally considered safe, even at doses exceeding the recommended dietary allowance (RDA); however, adverse effects are more likely to occur with higher doses. The tolerable upper intake level (UL) in healthy people is 1000 mg daily, equivalent to 1100 IU of synthetic vitamin E (all-rac-alpha-tocopherol) or 1500 IU of natural vitamin E (RRR-alpha-tocopherol) (4668,4681,4713,4714,4844,89234,90067,90069,90072,19206)(63244,97075). Although there is some concern that taking vitamin E in doses of 400 IU (form unspecified) per day or higher might increase the risk of adverse outcomes and mortality from all causes (12212,13036,15305,16709,83339), most of this evidence comes from studies that included middle-aged or older patients with chronic diseases or patients from developing countries in which nutritional deficiencies are prevalent.

POSSIBLY UNSAFE ...when used orally in high doses. Repeated doses exceeding the tolerable upper intake level (UL) of 1000 mg daily are associated with significant side effects in otherwise healthy people (4844). ...when used intravenously in large doses. Large repeated intravenous doses of all-rac-alpha-tocopherol (synthetic vitamin E) were associated with decreased activity of clotting factors and bleeding in one report (3074). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adults who use e-cigarette, or vaping, products, which often contain vitamin E acetate. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Vitamin E acetate has been detected in most bronchoalveolar lavage samples taken from patients with EVALI. Other ingredients, including THC or nicotine, were also commonly found in samples. However, priority toxicants including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable in almost all samples. While this association shows a correlation between vitamin E acetate inhalation and lung injury, a causal link has not yet been determined, and it is not clear if other toxic compounds are also involved (101061,101062,102970).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Vitamin E has been safely used in children in amounts below the tolerable upper intake level (UL). The UL for healthy children is: 200 mg in children aged 1-3 years, 300 mg in children aged 4-8 years, 600 mg in children aged 9-13 years, and 800 mg in children aged 14-18 years. A UL has not been established for infants up to 12 months of age (23388).

CHILDREN: POSSIBLY UNSAFE
when used orally in doses above the UL due to increased risk of adverse effects (23388). ...when alpha-tocopherol is used intravenously in large doses in premature infants. Large intravenous doses of vitamin E are associated with an increased risk of necrotizing enterocolitis and sepsis in this population (85062,85083). ...when inhaled. E-cigarette, or vaping, product-use associated lung injury (EVALI) has occurred among adolescents and teenagers who use e-cigarette, or vaping, products. In some cases, this has resulted in death. The majority of patients with EVALI reported using tetrahydrocannabinol (THC)-containing products in the 3 months prior to the development of symptoms. Constituents in E-cigarette or vaping products with the potential to cause lung injury or impaired lung function include lipids, such as vitamin E acetate. Vitamin E acetate has been detected in all bronchoalveolar lavage samples taken from patients with EVALI. No other ingredient, including THC or nicotine, was found in all samples, and other ingredients, including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable This shows that vitamin E acetate is at the primary site of lung injury. A causal link has not yet been described and it is not clear if other compounds are also involved (101061,101062).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately. The tolerable upper intake level (UL) during pregnancy is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older. However, maternal supplementation is not generally recommended unless dietary vitamin E falls below the RDA (4260). No serious adverse effects were reported with oral intake of 400 IU per day starting at weeks 9-22 of pregnancy in healthy patients or those at high risk for pre-eclampsia (3236,97075), or with 600-900 IU daily during the last two months of pregnancy (4260). However, some preliminary evidence suggests that taking vitamin E supplements might be harmful when taken in early pregnancy. A case-control study found that taking a vitamin E supplement during the first 8 weeks of pregnancy is associated with a 1.7-9-fold increase in odds of congenital heart defects (16823). However, the exact amount of vitamin E consumed during pregnancy in this study is unclear. Until more is known, advise patients to avoid taking a vitamin E supplement in early pregnancy unless needed for an appropriate medical indication.

LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL). The UL during lactation is 800 mg for those 14-18 years of age and 1000 mg for those 19 years and older (4844).

LACTATION: POSSIBLY UNSAFE
when used orally in amounts that exceed the UL due to increased risk of adverse effects (4844).

WHEATGRASS (organic Wheat Grass fine ground powder)

LIKELY SAFE ...when consumed in amounts commonly found in foods (5286).

POSSIBLY SAFE ...when wheatgrass juice is taken orally and appropriately in medicinal amounts. Wheatgrass juice 60-100 mL daily has been used safely for up to 18 months (11165,85601,104878,104879). ...when wheatgrass cream is used topically. Wheatgrass 10% cream has been used safely for up to 6 weeks (85602). There is insufficient reliable information available about the long-term safety of wheatgrass when used medicinally.

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

Interactions with Drugs view details

Below is general information about the interactions of the known ingredients contained in the product Daily Veggie. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

BARLEY (organic Barley Grass fine ground powder)

TRICLABENDAZOLE (Egaten)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, barley might decrease the clinical effects of triclabendazole.

Details

Animal research suggests that a diet supplemented with barley can reduce the bioavailability of triclabendazole when taken concomitantly (23884). This effect has not been shown in humans.

None known.

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Unlikely • Level of Evidence = D

Theoretically, spirulina blue-green algae might increase the risk of bleeding if used with other anticoagulant or antiplatelet drugs. However, this is unlikely.

Details

Spirulina blue-green algae have shown antiplatelet and anticoagulant effects in vitro (18311,18312,75892,92162,92163). However, one preliminary study in 24 patients receiving spirulina blue-green algae 2.3 grams daily for 2 weeks showed no effect on platelet activation or measures of clotting time (97202).

ANTIDIABETES DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Theoretically, taking blue-green algae with antidiabetes drugs might increase the risk of hypoglycemia.

Details

Human research shows that spirulina blue-green algae can have hypoglycemic effects in patients with diabetes, at least some of whom were using antidiabetes drugs (18299). However, blue-green algae does not seem to improve glycated hemoglobin (HbA1c) levels in patients with diabetes (102689,109970). A meta-analysis of animal studies also suggests that spirulina blue-green algae have hypoglycemic effects (109970).

IMMUNOSUPPRESSANTS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, concurrent use of blue-green algae might interfere with immunosuppressive therapy.

Details

Blue-green algae have been shown to stimulate the immune system (2534,10267).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Theoretically, broccoli might reduce the levels and effects of drugs metabolized by CYP1A2.

Details

Pharmacokinetic research in humans shows that eating 500 grams of fresh broccoli daily for 6-12 days can increase CYP1A2 activity by 10% to 200% (19608,95722). Induction of CYP1A2 activity by broccoli is attributed to its glucosinolate constituents (19608).

CYTOCHROME P450 2A6 (CYP2A6) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Theoretically, broccoli might reduce the levels and effects of drugs metabolized by CYP2A6.

Details

Pharmacokinetic research in humans shows that eating 500 grams of broccoli daily for 6 days increases CYP2A6 activity by 135% to 550%. Induction of CYP2A6 activity is attributed to its glucosinolate constituents (19608).

BRUSSELS SPROUT (organic Brussels Sprouts powder)

ACETAMINOPHEN (Tylenol, others)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Mild • Occurrence = Probable • Level of Evidence = B

A cabbage and Brussels sprout-containing diet can increase metabolism and decrease levels of acetaminophen. In clinical research, a diet that includes daily consumption of cabbage and Brussels sprout decreases acetaminophen levels by as much as 16%. This appears to occur due to a boost of elimination through glucuronide conjugation (3952).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Animal research suggests that Brussels sprout can induce cytochrome P450 1A2 (CYP1A2) activity (26183). Theoretically, Brussels sprout might increase the clearance and decrease the effects of drugs metabolized by CYP1A2. Some drugs metabolized by CYP1A2 include clozapine (Clozaril), cyclobenzaprine (Flexeril), fluvoxamine (Luvox), haloperidol (Haldol), imipramine (Tofranil), mexiletine (Mexitil), olanzapine (Zyprexa), pentazocine (Talwin), propranolol (Inderal), tacrine (Cognex), theophylline, zileuton (Zyflo), zolmitriptan (Zomig), and others.

GLUCURONIDATED DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

A cabbage and Brussels sprout-containing diet seems to boost elimination through glucuronide conjugation (3952). Theoretically, these foods might also lower levels of other drugs that are metabolized through glucuronide conjugation, including acetaminophen (Tylenol, others) and oxazepam (Serax), haloperidol (Haldol), lamotrigine (Lamictal), morphine (MS Contin, Roxanol), zidovudine (AZT, Retrovir), and others.

OXAZEPAM (Serax)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

A diet that includes daily consumption of cabbage and Brussels sprout decreases oxazepam levels by as much as 17%. This appears to occur due to a boost of elimination through glucuronide conjugation (3952). Theoretically, Brussels sprout might also lower levels of other drugs that are metabolized through glucuronide conjugation including acetaminophen (Tylenol, others), haloperidol (Haldol), lamotrigine (Lamictal), morphine (MS Contin, Roxanol), zidovudine (AZT, Retrovir), and others.

WARFARIN (Coumadin)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = B

Preliminary clinical research shows that increasing Brussels sprout consumption by 400 grams daily can increase warfarin clearance rate by 27% and decrease plasma concentrations of warfarin by 16% (26182). Theoretically, consuming Brussels sprout while taking warfarin might decrease the effects of warfarin and increase the risk of blood clots in some people.

ACETAMINOPHEN (Tylenol, others)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Mild • Occurrence = Probable • Level of Evidence = B

Cabbage might increase clearance and reduce the effects of acetaminophen.

Details

A small clinical study shows that daily consumption of cabbage and Brussels sprout decreases acetaminophen levels by as much as 16%, with some evidence suggesting that this effect is due to increased elimination through glucuronide conjugation (3952).

ANTIDIABETES DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, cabbage might increase the risk of hypoglycemia when taken with antidiabetes drugs.

Details

Animal and in vivo research suggests that cabbage might have hypoglycemic effects (25424).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, cabbage might decrease levels of drugs metabolized by CYP1A2.

Details

Some animal research suggests that cabbage or its constituent indole-3-carbinol might increase drug metabolism and elimination by stimulating CYP1A2 activity (7176,7187,51183).

GLUCURONIDATED DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Theoretically, cabbage might increase clearance and decrease the effects of drugs metabolized through glucuronide conjugation.

Details

A small clinical study shows that daily consumption of cabbage and Brussels sprout decreases levels of some drugs metabolized through glucuronide conjugation (3952).

OXAZEPAM (Serax)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Cabbage might increase clearance and reduce the effects of oxazepam.

Details

A small clinical study shows that daily consumption of cabbage and brussels sprout decreases oxazepam levels by as much as 17%, with some evidence suggesting that this effect is due to increased elimination through glucuronide conjugation (3952).

WARFARIN (Coumadin)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, cabbage might decrease the anticoagulant effects of warfarin.

Details

Cabbage contains vitamin K. If consumed in large quantities, cabbage might decrease the anticoagulant effects of warfarin (19).

None known.

ACETAMINOPHEN (Tylenol, others)

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Possible • Level of Evidence = D

Theoretically, celery juice might increase the effects and side effects of acetaminophen.

Details

Animal research suggests that concomitant use of celery juice plus acetaminophen prolongs the effects of acetaminophen. This effect has been attributed to a decrease in hepatic cytochrome P450 activity (25362). However, other animal research shows that pretreatment with celery root extract protects against acetaminophen-induced acute liver failure (106487). These effects have not been reported in humans.

AMINOPYRINE

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Possible • Level of Evidence = D

Theoretically, celery juice might increase the effects and side effects of aminopyrine.

Details

Animal research suggests that concomitant use of celery juice plus aminopyrine prolongs the effects of aminopyrine. This effect has been attributed to a decrease in hepatic cytochrome P450 activity (25362). This effect has not been reported in humans.

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, celery root might increase the risk of bleeding when taken with anticoagulant/antiplatelet drugs.

Details

Celery root contains the constituents falcarinol and falcarindiol. Laboratory research suggests that these constituents can inhibit platelet aggregation (6048,40991). This effect has not been reported in humans.

ANTIHYPERTENSIVE DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Theoretically, celery seed extract might have additive effects with antihypertensive drugs.

Details

Clinical research suggests that taking celery seed extract may reduce daytime systolic blood pressure by about 12 mmHg compared to less than 1 mmHg with placebo (110755).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, celery might increase levels of drugs metabolized by CYP1A2.

Details

In vitro and animal research suggests that constituents of celery can inhibit CYP1A2 (68176). This effect has not been reported in humans.

LEVOTHYROXINE (Synthroid, others)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, celery seed might decrease the effects of levothyroxine.

Details

Several cases of hypothyroidism with low T4 levels have been reported in people who were previously stabilized on levothyroxine and then started taking celery seed tablets. They presented with symptoms such as lethargy, bloating, and dry skin, and recovered when celery seed was stopped (10646). However, celery stem and leaf has been associated with case reports of hyperthyroidism in patients with no pre-existing thyroid disorders (102912,102914).

LITHIUM

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Theoretically, celery might reduce excretion and increase levels of lithium due to potential diuretic effects.

Details

Celery is thought to have diuretic properties (4,6). However, this effect has not been confirmed in humans.

PHOTOSENSITIZING DRUGS

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Possible • Level of Evidence = D

Theoretically, celery might increase the risk of photosensitivity reactions when taken with photosensitizing drugs.

Details

Laboratory research shows that celery contains photosensitizing agents such as phenols and psoralens (6178,40894,40917,41073,41121).

VENLAFAXINE (Effexor)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, celery root extract might increase blood levels of venlafaxine.

Details

There is one case report of a patient who experienced medication-induced bipolar disorder after beginning to take celery root extract 1000 mg daily along with venlafaxine 75 mg and St. John's wort 600 mg daily. Symptoms included confusion, speech abnormalities, manic affect, and visual hallucinations. The plasma level of venlafaxine was 476.8 ng/mL (normal range 195-400 ng/mL). It is theorized that celery root increased venlafaxine levels by inhibiting cytochrome P450 2D6 (92854).

ANTIDIABETES DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

In an animal study, an aqueous extract of collard leaves and stems has been shown to reduce glucose levels. Collard extract 60 mg/kg lowers blood glucose levels in a rat model of diabetes after both single- and multi-dose oral administration similarly to glibenclamide 5 mg/kg (105712). Theoretically, collard extract might have additive effects when used concomitantly with antidiabetes drugs and may increase the risk of hypoglycemia. Monitor blood glucose levels closely. Dose adjustments may be necessary. Some antidiabetes drugs include glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, Micronase), insulin, pioglitazone (Actos), rosiglitazone (Avandia), chlorpropamide (Diabinese), glipizide (Glucotrol), and tolbutamide (Orinase).

FOLIC ACID

5-FLUOROURACIL

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, high doses of folic acid might increase the toxicity of 5-fluorouracil.

Details

Increases in gastrointestinal side effects of 5-fluorouracil, such as stomatitis and diarrhea, have been described in two clinical studies when leucovorin, a form of folic acid, was administered with 5-fluorouracil (16845).

CAPECITABINE (Xeloda)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Use of high-dose folic acid might contribute to capecitabine toxicity.

Details

Clinical research suggests that higher serum folate levels are associated with an increased risk for moderate or severe toxicity during capecitabine-based treatment for colorectal cancer (105402). Additionally, in one case report, taking folic acid 15 mg daily might have contributed to increased toxicity, including severe diarrhea, vomiting, edema, hand-foot syndrome, and eventually death, in a patient prescribed capecitabine (16837).

METHOTREXATE (Trexall, others)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Folic acid might reduce the efficacy of methotrexate as a cancer treatment when given concurrently.

Details

Methotrexate exerts its cytotoxic effects by preventing conversion of folic acid to the active form needed by cells. There is some evidence that folic acid supplements reduce the efficacy of methotrexate in the treatment of acute lymphoblastic leukemia, and theoretically they could reduce its efficacy in the treatment of other cancers (9420). Advise cancer patients to consult their oncologist before using folic acid supplements. In patients treated with long-term, low-dose methotrexate for rheumatoid arthritis (RA) or psoriasis, folic acid supplements can reduce the incidence of side effects, without reducing efficacy (768,2162,4492,4493,4494,4546,9369).

PHENOBARBITAL (Luminal)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Folic acid might have antagonistic effects on phenobarbital and increase the risk for seizures.

Details

Folic acid can have direct convulsant activity in some people, reversing the effects of phenobarbital and worsening seizure control (4427,9357,9358). Monitor closely for increased seizure activity.

PHENYTOIN (Dilantin)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Folic acid might reduce serum levels of phenytoin in some patients.

Details

Folic acid may be a cofactor in phenytoin metabolism (4471). Folic acid, in doses of 1 mg daily or more, can reduce serum levels of phenytoin in some patients (4471,4477,4531,4536). Increases in seizure frequency have been reported. If folic acid supplements are added to established phenytoin therapy, monitor serum phenytoin levels closely. If phenytoin and folic acid are started at the same time and continued together, adverse changes in phenytoin pharmacokinetics are avoided (4471,4472,4473,4531). Note that phenytoin also reduces serum folate levels.

PRIMIDONE (Mysoline)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Folic acid might have antagonistic effects on primidone and increase the risk for seizures.

Details

Folic acid can have direct convulsant activity in some people, reversing the effects of primidone and worsening seizure control (4427,9357,9358). Monitor closely for increased seizure activity. Note that primidone also reduces serum folate levels.

PYRIMETHAMINE (Daraprim)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Folic acid might antagonize the effects of pyrimethamine.

Details

Folic acid can antagonize the antiparasitic effects of pyrimethamine against toxoplasmosis and Pneumocystis carinii pneumonia. Folic acid doesn't antagonize the effects of pyrimethamine in the treatment of malaria, because malarial parasites cannot use exogenous folic acid. Use folinic acid as an alternative to folic acid when indicated (9380).

AMIODARONE (Cordarone)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Theoretically, combining Fucus vesiculosus with amiodarone might cause excessively high iodine levels.

Details

Fucus vesiculosus contains high concentrations of iodine (7135). Amiodarone contains 37.3% iodine and can increase iodine levels. Concomitant use might increase the risk of having excessive iodine levels and adversely affecting thyroid function (7135,17574). Monitor thyroid function.

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Minor Be watchful with this combination.

Severity = Moderate • Occurrence = Unlikely • Level of Evidence = D

Theoretically, taking Fucus vesiculosus with antiplatelet or anticoagulant drugs might increase the risk of bruising and bleeding.

Details

In vitro evidence suggests that a constituent of Fucus vesiculosus, known as fucoidan, has anticoagulant effects (12797,74149,74183,74240). However, in clinical research, fucoidan does not seem to have significant anticoagulant activity when taken orally, possibly due to poor absorption (74183).

ANTITHYROID DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Due to its iodine content, Fucus vesiculosus might alter the effects of antithyroid drugs.

Details

Fucus vesiculosus contains high concentrations of iodine (7135). Iodine in high doses has been reported to cause both hyperthyroidism and hypothyroidism, depending on the individual's past medical history. Taking Fucus vesiculosus while using antithyroid drugs could alter the effects of the antithyroid drugs (2138,17574).

CYTOCHROME P450 2C8 (CYP2C8) SUBSTRATES

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Possible • Level of Evidence = D

Theoretically, concomitant use of Fucus vesiculosus with CYP2C8 substrates might increase the risk for adverse effects.

Details

In vitro research shows that fucoidan, a constituent of Fucus vesiculosus, inhibits CYP2C8 (97791). 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, concomitant use of Fucus vesiculosus with CYP2C9 substrates might increase the risk for adverse effects.

Details

In vitro research shows that fucoidan, a constituent of Fucus vesiculosus, inhibits CYP2C9 (97791). 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, concomitant use of Fucus vesiculosus with CYP2D6 substrates might alter the effects of these substrates.

Details

In vitro research shows that fucoidan, a constituent of Fucus vesiculosus, both inhibits and induces CYP2D6 (97791). 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, concomitant use of Fucus vesiculosus with CYP3A4 substrates might increase the risk for adverse effects.

Details

In vitro research shows that fucoidan, a constituent of Fucus vesiculosus, inhibits CYP3A4 (97791). This interaction has not been reported in humans.

LITHIUM

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Concomitant use of Fucus vesiculosus and lithium has resulted in hyperthyroidism.

Details

There is a case of hyperthyroidism occurring in a patient taking Fucus vesiculosus and lithium (74217). Monitor thyroid hormones closely in patients taking lithium and Fucus vesiculosus concomitantly.

THYROID HORMONE

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Due to its iodine content, Fucus vesiculosus might alter the effects of thyroid hormone.

Details

Fucus vesiculosus contains high concentrations of iodine (7135). Iodine in high doses has been reported to cause both hyperthyroidism and hypothyroidism, depending on the individual's past medical history. Taking Fucus vesiculosus while using thyroid hormone could alter the effects of thyroid hormone.

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Garlic may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.

Details

Raw garlic and a variety of garlic extracts have antiplatelet activity and can increase prothrombin time (586,616,1874,3234,4366,4802,4803,51397,96013).

ANTIDIABETES DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Theoretically, taking garlic with antidiabetes drugs might increase the risk of hypoglycemia.

Details

Clinical research suggests that garlic and garlic extract lower blood glucose levels in healthy and diabetic individuals (51463,96004).

ANTIHYPERTENSIVE DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, taking garlic with antihypertensive drugs might increase the risk of hypotension.

Details

In human research, both garlic and garlic extracts have blood pressure-lowering effects (277,278,279,1873,4787,6897,16605,51414,51442,51669)(88386,88398,96007).

ATAZANAVIR (Reyataz)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, garlic might decrease levels and effects of atazanavir.

Details

In a case report, a patient consuming six stir-fried garlic cloves three times weekly developed suboptimal atazanavir levels and increases in HIV viral load. While the exact cause of this interaction is unclear, there is speculation that garlic might decrease the intestinal absorption of atazanavir or increase its metabolism by inducing cytochrome P450 3A4 (CYP3A4) (88388). Until more is known, advise patients not to consume large amounts of garlic while taking atazanavir.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Garlic might increase levels of drugs metabolized by CYP2E1.

Details

Clinical research suggests garlic oil can inhibit the activity of CYP2E1 by 39% (10847). Use garlic oil cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Theoretically, garlic products containing allicin might induce intestinal CYP3A4 and inhibit hepatic CYP3A4. This may increase or decrease levels of drugs metabolized by CYP3A4.

Details

Some human research suggests that garlic may induce INTESTINAL CYP3A4, reducing levels of drugs metabolized by this enzyme. This is primarily based on a study showing that taking a specific allicin-containing garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces saquinavir levels by approximately 50%. It is speculated that the allicin constituent induced CYP3A4 in the gut mucosa (7027,93578). Another study shows that giving docetaxel intravenously, bypassing the CYP3A4 enzymes in the gut mucosa, along with the same specific garlic product for 12 consecutive days, does not affect docetaxel levels (17221). Conversely, there is concern that garlic may inhibit HEPATIC CYP3A4. In a single case report, increased tacrolimus levels and liver injury occurred in a liver transplant patient after taking a specific garlic supplement (Garlicin Cardio, Nature's Way) at up to three times the manufacturer recommended dose for 7 days (96010). Several other studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506).

ISONIAZID

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, garlic might decrease levels of isoniazid.

Details

Animal research suggests that an aqueous extract of garlic reduces isoniazid levels by about 65%. Garlic reduced the maximum concentration (Cmax) and area under the curve (AUC), but not the half-life, of isoniazid. This suggests that garlic extract might inhibit isoniazid absorption across the intestinal mucosa (15031); however, the exact mechanism of this potential interaction is not known.

PROTEASE INHIBITORS (PIs)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = B

Theoretically, garlic products containing allicin might decrease levels of PIs.

Details

Protease inhibitors are metabolized by cytochrome P450 3A4 (CYP3A4) isoenzymes. There is concern that garlic products containing allicin might induce intestinal CYP3A4, reducing plasma levels of protease inhibitors. This is primarily based on a study showing that taking a specific garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces levels of saquinavir, a PI, by approximately 50%. It is speculated that the allicin constituent induce CYP3A4 in the gut mucosa (7027,93578). Several studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506).

SAQUINAVIR (Fortovase, Invirase)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = B

Theoretically, garlic containing allicin might decrease levels of saquinavir.

Details

Saquinavir is a substrate of cytochrome P450 3A4 (CYP3A4) isoenzymes. There is concern that garlic products containing allicin might induce intestinal CYP3A4 and cause subtherapeutic levels of saquinavir. This is primarily based on a pharmacokinetic study showing that taking a specific garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces saquinavir levels by approximately 50%. It is speculated that the allicin constituent induces CYP3A4 in the gut mucosa (7027,93578). Several pharmacokinetic studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506). Until more is known about this potential interaction, use garlic containing allicin cautiously in patients taking saquinavir.

SOFOSBUVIR (Sovaldi)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, taking garlic with sofosbuvir might decrease its effectiveness.

Details

Animal research in rats shows that giving aged garlic extract 120 mg/kg orally daily for 14 days decreases the area under the concentration time curve (AUC) after a single sofosbuvir dose of 40 mg/kg by 36%, increases the clearance by 63%, and decreases the plasma concentrations at 1 and 8 hours by 35% and 58%, respectively. This interaction is hypothesized to be due to induction of intestinal P-glycoprotein expression by garlic (109524).

TACROLIMUS (Prograf)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = B

Theoretically, garlic might increase levels of tacrolimus.

Details

In one case report, a liver transplant patient taking tacrolimus experienced increased tacrolimus levels and liver injury after taking a specific garlic supplement (Garlicin Cardio, Nature's Way) at up to three times the manufacturer recommended dose for 7 days. It is speculated that garlic inhibited hepatic cytochrome P450 3A4 (CYP3A4), which increased plasma levels of tacrolimus (96010).

WARFARIN (Coumadin)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, garlic might increase the risk of bleeding with warfarin.

Details

Raw garlic and a variety of garlic extracts have antiplatelet activity and can increase prothrombin time (586,616,1874,3234,4366,4802,4803,51397). In addition, there is a report of two patients who experienced an increase in a previously stabilized international normalized ratio (INR) with concomitant garlic and warfarin use (51228,51631). However, this report has been subsequently debated due to limited clinical information. Other clinical studies have not identified an effect of garlic on INR, warfarin pharmacokinetics, or bleeding risk (15032,16416). More evidence is needed to determine the safety of using garlic with warfarin.

THYROID HORMONE

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, horseradish might interfere with the effects of thyroid hormone.

Details

Horseradish and other members of the cabbage and mustard family are associated with depressed thyroid function (4).

None known.

ACE INHIBITORS (ACEIs)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, laminaria might increase the risk of hyperkalemia when taken with ACEIs.

Details

Laminaria contains potassium (19).

AMIODARONE (Cordarone)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, combining laminaria with amiodarone might cause excessively high iodine levels.

Details

Amiodarone contains 37.3% iodine and can increase iodine levels. Concomitant use with laminaria supplements, some of which may contain as much as 1000 mcg iodine, might increase the risk of adverse effects from iodine, including altered thyroid function (9556,94046).

ANTITHYROID DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Due to its iodine content, laminaria might alter the effects of antithyroid drugs.

Details

Some laminaria supplements contain up to 1000 mcg of iodine (9556,94046). Iodine in high doses has been reported to cause both hyperthyroidism and hypothyroidism, depending on the individual's past medical history. Taking laminaria could theoretically alter the effects of antithyroid drugs.

DIGOXIN (Lanoxin)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, laminaria might increase the risk of hyperkalemia, which could increase the effects and adverse effects of digoxin.

Details

Laminaria contains potassium (19).

POTASSIUM-SPARING DIURETICS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, laminaria might increase the risk of hyperkalemia when taken with potassium-sparing diuretics.

Details

Laminaria contains potassium (19).

THYROID HORMONE

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Due to its iodine content, laminaria might alter the effects of thyroid hormone.

Details

LIPASE

None known.

ANTIDIABETES DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, oats may have additive effects with antidiabetic agents and might increase the risk of hypoglycemia.

Details

Consuming oats can decrease blood glucose in patients with diabetes (4980,4982,6266,103345). In those who require insulin, taking oats 100 grams daily for 2 days reduces the insulin dose required to achieve metabolic control (103336).

INSULIN

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Concomitant use of oats and insulin might increase the risk of hypoglycemia.

Details

In patients with insulin-dependent type 2 diabetes, taking oats 100 grams daily for 2 days reduces the insulin dose required to achieve metabolic control (103336).

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, concomitant use of anticoagulant or antiplatelet drugs with onion might increase the risk of bleeding.

Details

In vitro research shows that onion inhibits platelet aggregation (19,66898).

ANTIDIABETES DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Concomitant use of antidiabetes drugs with onion may increase the risk of hypoglycemia.

Details

Animal research and clinical research shows that taking onion can lower blood glucose levels (19,66800,66812,66859,66982,67033,67043,67053,67072,95148,95160). Monitor blood glucose levels closely.

ASPIRIN

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Concomitant use of aspirin with onion may worsen onion allergy.

Details

In one case report, a patient with a mild onion allergy reported worsening allergy, including swelling and severe urticaria, after taking aspirin (5054).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Theoretically, taking onion might increase the levels and clinical effects of drugs metabolized by CYP2E1.

Details

Animal research shows that taking onion powder inhibits CYP2E1 (19653). However, this interaction has not been reported in humans.

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Animal research suggests that parsley has antiplatelet effects (68209). Theoretically, concomitant use of parsley with other anticoagulant/antiplatelet drugs might reduce platelet aggregation and increase the risk of bleeding.

Details

Some anticoagulant/antiplatelet drugs include aspirin, clopidogrel (Plavix), ticagrelor (Brilinta) diclofenac (Voltaren, Cataflam), ibuprofen (Advil, Motrin), naproxen (Anaprox, Naprosyn), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, warfarin (Coumadin), and others.

ANTIDIABETES DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Animal research suggests that parsley might decrease blood sugar (13174,68131,68153,68162). Theoretically, parsley might have additive effects with antidiabetes drugs and increase the risk of hypoglycemia. Monitor blood glucose levels closely. Dose adjustments might be necessary. Some antidiabetes drugs include glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, Micronase), insulin, pioglitazone (Actos), rosiglitazone (Avandia), and others.

ASPIRIN

Interaction Rating = Minor Be watchful with this combination.

Severity = Moderate • Occurrence = Unlikely • Level of Evidence = D

Concomitant intake with parsley might augment parsley allergy. There is one case report of severe urticaria and swelling in a person with a known mild parsley allergy after consuming parsley and aspirin (5054).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Laboratory research suggests that parsley can inhibit cytochrome P450 1A2 (CYP1A2) (68176). Theoretically concomitant use may increase the levels of CYP1A2 substrates.

Details

Some drugs metabolized by CYP1A2 include amitriptyline (Elavil), haloperidol (Haldol), ondansetron (Zofran), propranolol (Inderal), theophylline (Theo-Dur, others), verapamil (Calan, Isoptin, others), and others.

DIURETIC DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Animal research suggests that parsley seed extract increases urine elimination (68119). Theoretically, parsley leaf and root might interfere with diuretic therapy due to aquaretic effects (512).

Details

Some diuretic drugs include chlorothiazide (Diuril), chlorthalidone (Thalitone), furosemide (Lasix), hydrochlorothiazide (HCTZ, HydroDiuril, Microzide), spironolactone (Aldactone), triamterene (Dyrenium), and others.

PENTOBARBITAL (Nembutal)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Animal research suggests that parsley juice prolongs the action of pentobarbital, perhaps by decreasing cytochrome P450 levels (25362). It is not known if this occurs in humans or if this applies to other barbiturates or sedatives.

SIROLIMUS (Rapamune)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Large quantities of parsley might increase sirolimus levels. In one case report, an adult female with a history of kidney transplant presented with elevated blood sirolimus levels, approximately 4-7 times greater than previous measures, after daily consumption of a juice containing approximately 30 grams of parsley for 7 days. Sirolimus levels returned to normal a week after the parsley juice was discontinued (106010).

WARFARIN (Coumadin)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, large amounts of parsley leaf and root might interfere with oral anticoagulant therapy with warfarin, due to vitamin K contained in parsley (19).

PHYTASE

None known.

None known.

LITHIUM

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Pumpkin might reduce excretion and increase levels of lithium.

Details

Pumpkin is thought to have diuretic properties (92383). Theoretically, this might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased.

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Selenium may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.

Details

Clinical research suggests that taking selenium 10 mcg/kg/day can increase bleeding times by increasing prostacyclin production, which inhibits platelet activity (14540). Other clinical research suggests that taking selenium 75 mcg daily, in combination with ascorbic acid 600 mg, alpha-tocopherol 300 mg, and beta-carotene 27 mg, reduces platelet aggregation (74406).

BARBITURATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, selenium might prolong the sedating effects of barbiturates.

Details

Laboratory research suggests that selenium can inhibit the hepatic metabolism of barbiturates (14601,14602). Selenium seems to prolong the sedative effect of pentobarbital in animal models (14601).

CONTRACEPTIVE DRUGS

Interaction Rating = Minor Be watchful with this combination.

Severity = Insignificant • Occurrence = Possible • Level of Evidence = B

Contraceptive drugs might increase levels of selenium, although the clinical significance of this effect is unclear.

Details

Some research suggests that oral contraceptives increase serum selenium levels in women taking oral contraceptives; however, other research shows no change in selenium levels (14544,14545,14546,101343). It is suggested that an increase could be due to increased carrier proteins, indicating a redistribution of selenium rather than a change in total body selenium (14545).

GOLD SALTS

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Possible • Level of Evidence = D

Gold salts might interfere with selenium activity in tissues.

Details

Gold forms complexes with selenium, altering its tissue distribution. Theoretically, this might prevent the normal activity of selenium and produce effects equivalent to deficiency (14547,14548).

IMMUNOSUPPRESSANTS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, selenium supplementation may reduce the effectiveness of immunosuppressant therapy.

Details

In vitro research and preliminary clinical evidence suggests that selenium may stimulate the immune system (74483,74445).

NIACIN

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Possible • Level of Evidence = A

Selenium might reduce the beneficial effects of niacin on high-density lipoprotein (HDL) levels.

Details

A combination of niacin and simvastatin (Zocor) effectively raises HDL cholesterol levels in patients with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% in patients with coronary disease (7388,11537). It is not known whether this adverse effect is due to a single antioxidant such as selenium, or to the combination. It also is not known whether it will occur in other patient populations.

WARFARIN (Coumadin)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, selenium might interfere with warfarin activity.

Details

Animal research suggests that selenium can increase warfarin activity. Selenium might interact with warfarin by displacing it from albumin binding sites, reducing its metabolism in the liver, or by decreasing production of vitamin K-dependent clotting factors (14541). Selenium can also prolong bleeding times in humans by increasing prostacyclin production, which inhibits platelet activity (14540).

WARFARIN (Coumadin)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Spinach contains vitamin K, which can interfere with the activity of warfarin.

Details

In human research, although eating spinach with one meal does not result in coagulation test results outside the therapeutic range, daily consumption for one week necessitates dose adjustment of warfarin (19600). Individuals using anticoagulants should consume a consistent daily amount of spinach to maintain the effect of anticoagulant therapy (19).

None known.

VITAMIN A

HEPATOTOXIC DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = C

Theoretically, taking high doses of vitamin A in combination with other potentially hepatotoxic drugs might increase the risk of liver disease.

Details

The tolerable upper intake level (UL) is the highest level of intake that is likely to pose no risk of adverse effects. Doses of vitamin A above the UL can cause hepatotoxicity, ranging from elevated liver enzymes to liver failure (7135,82554).

RETINOIDS

Interaction Rating = Major Do not take this combination.

Severity = High • Occurrence = Probable • Level of Evidence = D

Concomitant use of retinoids with vitamin A supplements might produce supratherapeutic vitamin A levels.

Details

Retinoids, which are vitamin A derivatives, could have additive toxic effects when taken with vitamin A supplements (3046).

TETRACYCLINE ANTIBIOTICS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, taking tetracycline antibiotics with high doses of vitamin A can increase the risk of pseudotumor cerebri.

Details

Benign intracranial hypertension (pseudotumor cerebri) can occur with tetracyclines and with acute or chronic vitamin A toxicity. Case reports suggest that taking tetracyclines and vitamin A concurrently can increase the risk of this condition (10545,10546,10547). Avoid high doses of vitamin A in people taking tetracyclines chronically.

WARFARIN (Coumadin)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, high doses of vitamin A could increase the risk of bleeding with warfarin.

Details

Vitamin A toxicity is associated with hemorrhage and hypoprothrombinemia, possibly due to vitamin K antagonism (505). Advise patients taking warfarin to avoid doses of vitamin A above the tolerable upper intake level of 10,000 IU/day for adults.

VITAMIN E

ALKYLATING AGENTS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, antioxidant effects of vitamin E might reduce the effectiveness of alkylating agents.

Details

There's concern that antioxidants could reduce the activity of chemotherapy drugs which generate free radicals, such as cyclophosphamide, chlorambucil, carmustine, busulfan, and thiotepa (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin E have on chemotherapy. Advise patients to consult their oncologist before using vitamin E supplements, especially in high doses.

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = B

Concomitant use of vitamin E and anticoagulant or antiplatelet agents might increase the risk of bleeding.

Details

Vitamin E seems to inhibit of platelet aggregation and antagonize the effects of vitamin K-dependent clotting factors (4733,4844,11580,11582,11583,11584,11586,112162). These effects appear to be dose-dependent, and are probably only likely to be clinically significant with doses of at least 800 units daily (11582,11585). Mixed tocopherols, such as those found in food, might have a greater antiplatelet effect than alpha-tocopherol (10364). RRR alpha-tocopherol (natural vitamin E) 1000 IU daily antagonizes vitamin K-dependent clotting factors (11999). Advise patients to avoid high doses of vitamin E, especially in people with low vitamin K intake or other risk factors for bleeding.

ANTITUMOR ANTIBIOTICS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, antioxidant effects of vitamin E might reduce the effectiveness of antitumor antibiotics.

Details

There's concern that antioxidants could reduce the activity of antitumor antibiotic drugs such as doxorubicin, which generate free radicals (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin E have on chemotherapy involving antitumor antibiotics. Advise patients to consult their oncologist before using vitamin E supplements, especially in high doses.

CYCLOSPORINE (Neoral, Sandimmune)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Unlikely • Level of Evidence = B

A specific form of vitamin E might increase absorption and levels of cyclosporine.

Details

There is some evidence that one specific formulation of vitamin E (D-alpha-tocopheryl-polyethylene glycol-1000 succinate, TPGS, tocophersolan, Liqui-E) might increase absorption of cyclosporine. This vitamin E formulation forms micelles which seems to increase absorption of cyclosporine by 40% to 72% in some patients (624,625,10368). However, this interaction is unlikely to occur with the usual forms of vitamin E.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, vitamin E might induce metabolism of CYP3A4, possibly reducing the levels CYP3A4 substrates.

Details

Vitamin E appears to bind with the nuclear receptor, pregnane X receptor (PXR), which results in increased expression of CYP3A4 (13499,13500). Although the clinical significance of this is not known, use caution when considering concomitant use of vitamin E and other drugs affected by these enzymes.

NIACIN

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Possible • Level of Evidence = A

Vitamin E might decrease the beneficial effects of niacin on high-density lipoprotein (HDL) cholesterol levels.

Details

A combination of niacin and simvastatin (Zocor) effectively raises high-density lipoprotein (HDL) cholesterol levels in people with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% (7388,11537). Vitamin E alone combined with a statin does not seem to decrease HDL levels (11286,11287). It is not known whether the adverse effect on HDL is due to one of the other antioxidants or to the combination. It also is not known whether it will occur in other patient populations.

SELUMETINIB (Koselugo)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Taking selumetinib with vitamin E can result in a total daily dose of vitamin E that exceeds safe limits and therefore might increase the risk of bleeding.

Details

Selumetinib contains 48-54 IU vitamin E per capsule (102971). The increased risk of bleeding with vitamin E appears to be dose-dependent (11582,11585,34577). Be cautious when using selumetinib in combination with supplemental vitamin E, especially in patients at higher risk of bleed, such as those with chronic conditions and those taking antiplatelet drugs (102971).

WARFARIN (Coumadin)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = B

Using vitamin E with warfarin might increase the risk of bleeding.

Details

Due to interference with production of vitamin K-dependent clotting factors, use of more than 400 IU of vitamin E daily with warfarin might increase prothrombin time (PT), INR, and the risk of bleeding, (91,92,93). At a dose of 1000 IU per day, vitamin E can antagonize vitamin K-dependent clotting factors even in people not taking warfarin (11999). Limited clinical evidence suggests that doses up to 1200 IU daily may be used safely by patients taking warfarin, but this may not be applicable in all patient populations (90).

WHEATGRASS (organic Wheat Grass fine ground powder)

ANTIDIABETES DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Some animal research shows that wheatgrass lowers blood glucose and stimulates the release of insulin from beta-cells (93018, 93019). Theoretically, wheatgrass might decrease blood glucose and have additive effects in patients treated with antidiabetes drugs, increasing the risk for hypoglycemia. Dose adjustments to diabetes medications may be necessarily. Some antidiabetes drugs include glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, Micronase), insulin, metformin (Glucophage), pioglitazone (Actos), rosiglitazone (Avandia), and others.

Report an Adverse Reaction to Daily Veggie

Adverse Effects view details

Below is general information about the adverse effects of the known ingredients contained in the product Daily Veggie. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

BARLEY (organic Barley Grass fine ground powder)

General ...Orally, barley is well tolerated.
Most Common Adverse Effects:
Orally: Abdominal distension, bloating, flatulence, unpleasant taste. Allergic reactions in sensitive individuals.
Topically: Allergic reactions in sensitive individuals.

Dermatologic ...Topically, barley malt contained in beer has been reported to cause contact dermatitis (33762). After occupational exposure, barley has been reported to cause contact dermatitis of the eyelids and extremities, as well as contact urticaria (33735,33770,33774).

Gastrointestinal ...When consumed orally, barley provides fiber. Increasing fiber in the diet can cause flatulence, bloating, abdominal distention, and unpleasant taste. To minimize side effects, doses should be slowly titrated to the desired level. Adverse effects usually subside with continued use (12514).
Barley contains gluten. In patients with biopsy-proven celiac disease, consuming barley can cause gastrointestinal upset and impairment of xylose excretion (33763,33772).

Immunologic ...Orally, consumption of beer has been reported to cause allergic reactions in sensitive individuals (33722,33724). Symptoms included tingling in the face, lip, and tongue, angioedema, generalized urticaria, chest tightness, dyspnea, cough, fainting, and rhinoconjunctivitis. It can also cause anaphylaxis in sensitive individuals (317). Topically and with occupational exposure, barley has been reported to cause contact dermatitis and rash (33762,33735,33770,33774).
"Bakers' asthma" is an allergic response resulting from the inhalation of cereal flours by workers in the baking and milling industries, and has been reported to occur after barley flour exposure (1300,33756,33760). Cross-allergenicity has been shown to exist between different cereals (33758).

Pulmonary/Respiratory ..."Bakers' asthma" is an allergic response resulting from the inhalation of cereal flours by workers in the baking and milling industries, and has been reported to occur after barley flour exposure (1300,33756,33760). Cross-allergenicity has been shown to exist between different cereals (33758).
By inhalation, barley flours may be a source of allergens in asthma (33764,33773). Inhalation of wild barley grass pollen may result in bronchial irritation or pneumonitis (33726,33755).

General ...Orally, beet seems to be well tolerated when used for medicinal purposes, short term.
Most Common Adverse Effects:
Orally: Red stools and red urine.
Serious Adverse Effects (Rare):
Orally: Hypocalcemia and kidney damage when ingested in large amounts.

Endocrine ...Theoretically, ingestion of large quantities of beets could lead to hypocalcemia because of the oxaluric acid content (18).

Gastrointestinal ...Orally, beet juice may cause red stools (94470,97726,100142,100145,105762). This red coloring of the stools is not harmful. Other less common gastrointestinal side effects include loose stools, constipation, and nausea (100149).

Genitourinary ...Orally, beet is known to produce red or pink urine (beeturia) in some people (32569,34134,94464,94470,97725,97726,100142,100145,100152,105762). However, this red coloring of the urine is not harmful.

Neurologic/CNS ...Orally, vivid dreams and worsening headaches have each occurred in one person in a clinical trial, although it is not clear if this is due to beet (97723).

Renal ...Theoretically, ingestion of large quantities of beets could lead to kidney damage due to its oxaluric acid content (18).

General ...Orally, spirulina blue-green algae seem to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal cramps, bloating, diarrhea, dizziness, fatigue, flatulence, headache, nausea, and vomiting.

Dermatologic ...Orally, a severe rash has been reported in a 49-year-old woman after taking a spirulina blue-green algae supplement (species and dose unknown). After stopping the supplement, inflammatory myopathy with muscle weakness and elevated creatine kinase occurred. The condition resolved with corticosteroid and cyclophosphamide treatment (75936). In another case report, an 82 year-old woman developed a blistering skin condition over a 2-year period while taking spirulina blue-green algae (A. platensis, dose unknown). She had partly hemorrhagic bullae, secreting erosions and macerations. These symptoms resolved when the supplement was stopped and the patient was treated with oral prednisone, topical silver sulfadiazine, and topical triamcinolone / neomycin (75921).

Gastrointestinal ...Orally, gastrointestinal complaints are amongst the most common adverse effects associated with spirulina blue-green algae, including nausea, vomiting, diarrhea, and abdominal cramps (19272,75924,91713,109969). Similarly, common adverse effects associated with the blue-green algae species Aphanizomenon flos-aquae are stomach upset, flatulence, diarrhea, and bloating (14842).

Hematologic ...Orally, three cases of mild gum bleeding and one case of mild bruising have been reported in patients taking spirulina blue-green algae (Cyactiv, Cerule LLC) 2. 3 grams daily (containing approximately 1 gram of phycocanin) for 2 weeks (97202).

Hepatic ...Orally, significant elevations of liver function tests within 2 weeks of starting a spirulina blue-green algae supplement (species and dose unknown) have been reported in a 52-year-old man stabilized on amlodipine, simvastatin, and acarbose. A biopsy showed feathery degeneration and ballooning of hepatic cells. Cholestasis was present, and an ex-vivo lymphocyte stimulation test for spirulina blue-green algae was positive. All drugs and the spirulina blue-green algae supplement were stopped, with return of the LFTs to normal (9172).

Immunologic ...Orally, urticarial rashes and pruritus have occurred as part of generalized allergic reactions to blue-green algae (91706,91711,91712).
In one case report, a 14-year-old male experienced anaphylaxis with urticaria, lip edema, and asthma 6 hours after taking five tablets of spirulina blue-green algae (A. platensis, strength unknown). He had a positive skin prick test. Oral challenge to an extract of the tablets, and IgE from his serum, reacted with the beta chain of C-phycocyanin from A. platensis (91712).
In another case report, a 17-year-old male with a history of multiple allergies developed rash, pruritus, angioedema, wheezing, and dyspnea within 10 minutes of taking spirulina blue-green algae (A. platensis) 300 mg. He had a positive skin test to A. platensis but no other ingredients of the tablets (91706).

Musculoskeletal ...Orally, after a 49-year-old woman stopped taking a spirulina blue-green algae supplement (species and dose unknown), the patient experienced inflammatory myopathy with muscle weakness and elevated creatine kinase. The condition resolved with corticosteroid and cyclophosphamide treatment (75936). Another case report describes acute rhabdomyolysis that occurred after consumption of spirulina (Arthrospira platensis, Hawaiian spirulina, Solgar Inc., Leonia, NJ) 3 grams daily for 1 month. The 24-year old man presented with weakness, myalgias, elevated creatine kinase and liver function tests, and myoglobinuria (75922).

General ...Broccoli is well tolerated when consumed as food. A thorough evaluation of safety outcomes when broccoli is taken as medicine has not been conducted.

Dermatologic ...Topically, allergic reactions to broccoli have caused contact dermatitis (14158).

Hepatic ...In one case report, a 56-year-old adult developed elevated transaminases, with alanine aminotransferase (ALT) 5. 8 times above normal, aspartate aminotransferase (AST) 2.4 times above normal, and gamma-glutamyl transpeptidase (GGT) 5.1 times above normal. This was thought to be related to the consumption of 800 mL of broccoli juice daily over a 4-week period. Values returned to normal 15 days after cessation of juice consumption (96191).

Immunologic ...Topically, allergic reactions to broccoli have caused contact dermatitis (14158).

BRUSSELS SPROUT (organic Brussels Sprouts powder)

General ...Orally, Brussels sprout is generally well-tolerated when consumed in dietary amounts. Eating Brussels sprout or other types of fermentable carbohydrates can cause flatulence (26470).

Gastrointestinal ...Orally, eating Brussels sprout or other types of fermentable carbohydrates can cause flatulence (26470).

General ...Topically, cabbage leaf seems to be well-tolerated.

Dermatologic ...Some preliminary clinical research shows that application of cabbage leaf wraps to knee joints for at least 2 hours daily for 4 weeks is generally well-tolerated. Of the 27 patients using cabbage leaf wraps in this study, one patient reported an itching and burning sensation during the application. This patient was later found to have shingles, which may explain the adverse event (93671). However, in another case, a patient applying fresh Savoy cabbage leaves on his knee to reduce joint pain reported pain and burning after 4 hours of use. Skin patch and prick tests did not indicate an allergic reaction, and the patient's lesion improved with wet dressings, topical antibiotics, and oral antibiotics (93675).

Immunologic ...Topically, cabbage may cause contact dermatitis (93675). Allergic reactions to cabbage-related vegetables are rare. However, anaphylactic reactions to broccoli and cauliflower have been reported. Because the surface proteins believed to cause allergic reactions to brocolli are also found in cabbage, some patients allergic to brocolli or other vegetables in the Brassicaceae family may also be allergic to cabbage (92516).

Other ...Topical application of cabbage leaves to the breasts has been reported to stain clothes and put off an unpleasant smell (6781,6782).

General ...Orally, carrot is well tolerated when consumed as a food. It also seems to be generally well-tolerated when consumed as a medicine. Some people are allergic to carrot; allergic symptoms include anaphylactic, cutaneous, respiratory, and gastrointestinal reactions such as hives, swelling of the larynx, asthma, or diarrhea (25820,93606,106560). In infants, excessive consumption of carrot products in nursing bottles has been reported to cause extensive caries in the primary teeth (25817).
Topically, carrot has been associated with a case of phytophotodermatitis (101716).

Dental ...Orally, feeding carrot juice to infants, with or without sugar- or acid-containing beverages, has been reported to damage teeth and cause dental caries (25817).

Dermatologic ...Orally, excessive consumption of carrots or carrot-containing products can cause yellowing of the skin, which results from increased beta-carotene levels in the blood (25817). Carrots may cause allergic reactions in some patients. Allergic responses to carrot-containing foods include skin reactions such as hives, erythema, swelling, and/or papules (25820,96306).

Gastrointestinal ...Orally, carrots may cause allergic reactions in some patients. Allergic responses to carrot-containing foods can include gastrointestinal symptoms, such as diarrhea (25820).

Immunologic ...Orally, carrots may cause allergic reactions in some patients (25820,96306,106560). Allergic responses to carrot-containing foods can include skin reactions such as hives, erythema, swelling, and/or papules (25820,96306). For one patient, treatment of skin lesions resolved after a month of oral antihistamines and topical steroids, and avoiding further contact with carrot (96306). Allergic responses to carrot-containing foods can also include gastrointestinal symptoms, such as diarrhea, and respiratory symptoms, such as swelling of the larynx or asthma (25820). In one case, a patient with a history of allergic rhinitis and asthma who had been successfully treated with subcutaneous immunotherapy and was tolerant of consumption of raw and cooked carrots developed rhinoconjunctivitis when handling carrots. Inhalation of dust particles and aerosols produced by food processing activities and containing allergens from the peel and pulp of carrots is thought to have sensitized the airway, producing a distinct form of respiratory food allergy in which there are typically no symptoms with ingestion (106560).
Topically, a female runner developed phytophotodermatitis, which was considered possibly associated with the inclusion of carrot in a sunscreen (Yes To Carrots Daily Facial Moisturizer with SPF 15; Yes to, Inc.) (101716).

Psychiatric ...Compulsive carrot eating is a rare condition in which the patient craves carrots. According to one case report, withdrawal symptoms include nervousness, cravings, insomnia, water brash, and irritability (25821).

General ...Orally, celery seems to be well tolerated.
Most Common Adverse Effects:
Orally: Photosensitivity. Oral allergy syndrome in sensitive individuals.
Topically: Photosensitivity. Contact dermatitis in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis in sensitive individuals.

Dermatologic ...Due to its psoralen content, contact with or ingestion of celery and exposure to ultraviolet radiation may cause photodermatitis (4,34347,40968,40969,40986,41085,41087,41143,41146,41151). Acute symptoms include skin eruption with edema and erythema; the main chronic symptom is hyperpigmentation at the eruption site (41093).
Celery can also cause contact or atopic dermatitis (19,41118,41124) and urticaria pigmentosa (40908).

Endocrine ...Celery has been associated with hyperthyroidism in otherwise healthy adults. In one case report a 36-year-old female presented with weight loss, blurred vision, nausea, palpitations, sweating, exophthalmos, elevated serum T4 levels, and low thyroid stimulating hormone (TSH) levels after taking 8 grams of a powdered celery extract for 78 days (102912). In another case report, a 48-year-old male presented with weight loss, exophthalmos, sweating, elevated serum T4 levels, and low TSH levels after taking 4 grams of dried celery leaves for 45 days (102914). In both of these cases, symptoms resolved and thyroid function tests normalized after discontinuing celery and completing a course of methimazole.
In contrast, several cases of hypothyroidism with low T4 levels have been reported in people who were previously stabilized on levothyroxine and then started taking celery seed tablets. They presented with symptoms such as lethargy, bloating, and dry skin, and recovered when celery seed was stopped (10646).

Gastrointestinal ...Symptoms of celery allergy have included oral allergy syndrome, characterized by itching and burning in the mouth and throat (41159,40977), and laryngeal edema (40953).

Immunologic ...Raw celery, cooked celery, and celery juice can all cause allergic reactions (40908,40926,41118,41131,92852,92855). Symptoms of celery allergy include laryngeal edema, skin reactions, an urticaria-edema-anaphylactic shock syndrome, celery-dependent exercise-induced anaphylaxis, and anaphylactic shock (40953,41100,41102,41107,41115,41124,41129,41135,41137,92852)(92855). Additionally, in clinical research, itchy throat has been reported in individuals taking celery seed powder (112410).
There is a case report of anaphylactic shock involving hypotension, tachycardia, and tachypnea in a patient who had ingested raw celery 15 minutes prior to symptom onset. The patient was treated with epinephrine, dexamethasone, and antazoline (92855). Another case report describes a patient with positive skin prick tests to celery, pollens including birch, chrysanthemum, mugwort, and ragweed, and to dust mites. When celery was consumed 30 minutes prior to exercise, the patient had an anaphylactic reaction that required treatment with intravenous pheniramine and corticosteroid, as well as nebulized albuterol (92852). Another patient with a history of anaphylactic reactions to undeclared celery in restaurant meals was able to undergo desensitization with gradually increasing oral doses of celery juice over several months, and then chronic daily ingestion of the juice to maintain hyposensitization (40908).

General ...Orally, collard is well tolerated when used in amounts found in foods. A thorough evaluation of safety outcomes related to the use of medicinal amounts of collard has not been conducted.

FOLIC ACID

General ...Orally, folic acid is generally well-tolerated in amounts found in fortified foods, as well as in supplemental doses of less than 1 mg daily.
Most Common Adverse Effects:
Orally: At doses of 5 mg daily - abdominal cramps, diarrhea, and rash. At doses of 15 mg daily - bitter taste, confusion, hyperactivity, impaired judgment, irritability, nausea, sleep disturbances.
Serious Adverse Effects (Rare):
Orally: Cancer (long-term use), cardiovascular complications, liver injury, seizures.
All ROAs: Allergic reactions such as bronchospasm and anaphylactic shock.

Cardiovascular ...There is some concern that high oral doses of folic acid might increase the risk of adverse cardiovascular outcomes. Clinical research shows that taking doses of 800 mcg to 1.2 mg/day might increase the risk of adverse cardiovascular events in patients with cardiovascular disease (12150,13482). High doses of folic acid might promote cell growth by providing large amounts of the biochemical precursors needed for cell replication. Overgrowth of cells in the vascular wall might increase the risk of occlusion (12150). Although some research suggests that use of folic acid might increase the need for coronary revascularization, analysis of multiple studies suggests that taking folic acid up to 5 mg/day for up to 24 months does not appear to affect coronary revascularization risk (90798).

Dermatologic ...Orally, folic acid 1-5 mg daily can cause rash (7225,90375,91319). Folic acid 15 mg daily can sometimes cause allergic skin reactions (15).

Gastrointestinal ...Orally, folic acid 5 mg daily can cause abdominal cramps and diarrhea (7225). Folic acid 15 mg daily can sometimes cause nausea, abdominal distention, flatulence, and bitter taste in the mouth (15). In children aged 6-30 months at risk of malnourishment, taking a nutritional supplement (Nutriset Ltd) enriched in folic acid 75-150 mcg daily, with or without vitamin B 12 0.9-1.8 mcg daily, for 6 months increases the likelihood of having persistent diarrhea (90391).

Hepatic ...Liver dysfunction, with jaundice and very high liver enzymes, occurred in a 30-year-old pregnant patient with severe nausea and vomiting taking a folic acid supplement (Folic acid, Nature Made) 400 mcg daily. Based on the timing of ingestion, the lack of other etiological factors, a positive drug-induced lymphocyte stimulation test, and liver function normalization once the folic acid had been stopped, the authors suggest the folic acid supplement was the cause. However, the authors did not determine which substance in the folic acid supplement was responsible and therefore it cannot be determined that folic acid itself was the cause (91309).

Neurologic/CNS ...Orally, folic acid 15 mg daily can sometimes cause altered sleep patterns, vivid dreaming, irritability, excitability, hyperactivity, confusion, and impaired judgment (15). Large doses of folic acid can also precipitate or exacerbate neuropathy in people deficient in vitamin B12 (6243). Use of folic acid for undiagnosed anemia has masked the symptoms of pernicious anemia, resulting in lack of treatment and eventual neurological damage (15). Patients should be warned not to self-treat suspected anemia. There is also some concern that consuming high amounts of folic acid from the diet and/or supplements might worsen cognitive decline in older people. A large-scale study suggests that people over 65 years of age, who consume large amounts of folic acid (median of 742 mcg/day), have cognitive decline at a rate twice as fast as those consuming smaller amounts (median of 186 mcg/day). It's not known if this is directly attributable to folic acid. It is theorized that it could be due to folic acid masking a vitamin B12 deficiency. Vitamin B12 deficiency is associated with cognitive decline (13068). More evidence is needed to determine the significance of this finding. For now, suggest that most patients aim for the recommended folic acid intake of 400 mcg/day.

Oncologic ...There is some concern that high dose folic acid might increase the risk of cancer, although research is unclear and conflicting. A large-scale population study suggests that taking a multivitamin more than 7 times per week with a separate folic acid supplement significantly increased the risk of prostate cancer (15607). Clinical research also shows that taking folic acid 1 mg daily increase the absolute risk of prostate cancer by 6.4% over a 10-year period when compared with placebo. However, those with a higher baseline dietary intake of folic acid had a lower rate of prostate cancer, but this was not statistically significant. Also, folate and folic acid intake in patients with prostate cancer is not associated with the risk of prostate cancer recurrence after radical prostatectomy (91317). However, it is possible that discrepancies are due to dietary folate versus folic acid intake. Large analyses of population studies suggest that while dietary folate/folic acid is not associated with prostate cancer, high blood folate/folic acid increases the risk of prostate cancer (50411,91316).
Additional clinical research shows that taking folic acid 800 mcg daily, in combination with vitamin B12 400 mcg, significantly increases the risk of developing cancer, especially lung cancer, and all-cause mortality in patients with cardiovascular disease (17041). However, this may be due to vitamin B12, as other observational research found that higher vitamin B12 levels are linked with an increased risk for lung cancer (102383). Meta-analyses of large supplementation trials of folic acid at levels between 0.5-2.5 mg daily also suggest an increased risk of cancer (50497,110318). Also, in elderly individuals, taking folic acid 400 mcg daily with vitamin B12 500 mcg daily increased the risk of cancer. The risk was highest in individuals over 80 years of age and in females and mainly involved gastrointestinal and colorectal cancers (90393).
Not all researchers suspect that high intake of folic acid supplements might be harmful. Some research suggests that increased dietary intake of folic acid, along with other nutrients, might be protective against cancer (16822). A meta-analysis of multiple clinical trials suggests that folic acid supplementation studies with folic acid levels between 500 mcg to 50 mg/day does not increase the risk of general or site-specific cancer for up to 7 years (91312,91321). Also, a post-hoc subgroup analysis of results from clinical research in adults with a history of recent stroke or ischemic attack suggests that taking folic acid, vitamin B12, and vitamin B6 does not increase cancer risk overall, although it was associated with an increased risk of cancer in patients who also had diabetes (90378).

Psychiatric ...Orally, folic acid 15 mg daily can sometimes cause exacerbation of seizure frequency and psychotic behavior (15).

Pulmonary/Respiratory ...Folic acid use in late pregnancy has been associated with an increased risk of persistent and childhood asthma at 3. 5 years in population research (50380). When taken pre-pregnancy or early in pregnancy, population research has not found an association with increased risk of asthma or allergies in childhood (90799,103979). Folic acid use in pregnancy has been associated with a slightly increased risk of wheeze and lower respiratory tract infections up to 18 months of age in population research (50328).

General ...When used orally, Fucus vesiculosus may be unsafe due to its iodine content. Topically, Fucus vesiculosus appears to be well tolerated.
Most Common Adverse Effects:
Orally: Goiter, hyperthyroidism, hypothyroidism.
Serious Adverse Effects (Rare):
Orally: Thyroid cancer.

Cardiovascular ...In one report, a young adult with obesity developed palpitations and syncope after taking an oral weight loss supplement containing a combination of Fucus vesiculosus, dandelion, and boldo for 3 weeks. The patient was found to have a prolonged QT interval on ECG and frequent episodes of sustained polymorphic ventricular tachycardia (14321). It is not clear whether Fucus vesiculosus, another ingredient, or the combination of ingredients is responsible for this adverse effect. The product was not analyzed to determine the presence of any potential toxic contaminants.

Endocrine ...Orally, Fucus vesiculosus can cause or exacerbate hyperthyroidism due to its high iodine content (12789,13061,74217). One case of hyperthyroidism has been reported for a 60-year-old patient taking lithium for bipolar disorder and a combination product containing Fucus vesiculosus 0.125 grams, cascara 0.170 grams, and Frangula 0.222 grams per tablet for laxative purposes. The patient had been taking one tablet of the combination laxative product daily for several years. Following discontinuation of the supplement, thyroid levels normalized (74217). Similar cases of hyperthyroidism have been reported for patients taking other seaweed-containing herbal supplements (Dream Shape; Ever Youth). Analyses of these supplements shows that these products contain triiodothyronine 1 mcg and thyroxine 3-4 mcg. In addition to seaweed, Dream Shape also contains hydrangea vine, maltose, chrysanthemum, Chinese matrimony vine, and sucrose, while Ever Youth contains radish, lotus leaf, chrysanthemum, hawthorn, senna tea, and Chinese matrimony vine (13061).
Orally, prolonged use of Fucus vesiculosus has been associated with hypothyroidism (13664). The iodine in Fucus vesiculosus can cause idiosyncratic reactions.
According to the Institute of Medicine Food and Nutrition Board, prolonged, high dietary intake of iodine is associated with goiter and an increased risk of thyroid cancer (7135).

Genitourinary ...A case of hemorrhagic cystitis characterized by dysuria and polyuria has been reported in a young adult who took a specific product (Slim-Kombu, Balestra and Mech) containing Fucus vesiculosus and 19 other herbal extracts orally for weight loss. Upon discontinuation, symptoms improved (46959). It is unclear if this effect was due to Fucus vesiculosus or other ingredients in the supplement.

Renal ...A case of hemorrhagic cystitis characterized by dysuria and polyuria has been reported in a young adult who took a specific product (Slim-Kombu, Balestra and Mech) containing Fucus vesiculosus and 19 other herbal extracts orally for weight loss. Upon discontinuation, symptoms improved (46959). It is unclear if this effect was due to Fucus vesiculosus or other ingredients in the supplement. Nephrotoxicity has been associated with oral intake of Fucus vesiculosus that was contaminated with arsenic (12800).

General ...Orally, garlic is generally well tolerated. Topically, garlic seems to be well tolerated. Intravenously, there is insufficient reliable information available about adverse effects.
Most Common Adverse Effects:
Orally: Abdominal pain, body odor, flatulence, malodorous breath, and nausea. Allergic reactions in sensitive individuals.
Topically: Burns and dermatitis with fresh garlic.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about increased risk of bleeding with garlic.

Dermatologic ...Orally, garlic may cause pruritus (51316,51474,107239), flushing, and acne (107239). Oral intake of a specific garlic product containing allicin (Allimax) has been associated with a case of pruritic rash (51474). Enteric-coated garlic tablets standardized to 1.5% allicin have also been associated with a case of pruritus (51316). Garlic has also been associated with a case of superficial pemphigus in a 49-year-old male with type 2 diabetes (51564). Garlic-induced oral ulcers have also been reported (51467).
Topically, garlic may cause contact dermatitis and urticaria (4833,5004,12635,51258,51265,51375,51403,51412,51459,51483)(51511,51512,51530,51616,51617,51618,111769), as well as contact cheilitis (51384). Fresh garlic may be more likely to elicit a reaction than garlic extract. Most reactions have resolved following withdrawal of garlic therapy. In one case report, applying crushed garlic on the neck to help ease a sore throat resulted in an itchy, burning, erythematous lesion in a young female patient. The lesion healed after one week of treatment with topical antibiotics, steroids, and antihistamine ointments (88390). Cases of occupational eczema or dermatitis have been reported in cooks (51303,51210), food handlers (51292), and caterers (51304). According to one case report, dermatitis appeared in chefs exposed to garlic (15033). Treatment with acitretin 25 mg daily or topical psoralen-ultraviolet A (PUVA) for 12 weeks proved effective in mitigating the symptoms. A 34-year-old female with a history of hand dermatitis and paronychia had a worsening of these conditions after peeling raw garlic. She had a positive skin patch test to fresh, raw garlic but not to any other tested allergens, and the conditions resolved when she avoided contact with garlic (105528). Topically, garlic may also cause chemical burns, usually within 12 hours of application. Second- and third-degree chemical burns have been reported in adults, children, and infants exposed to topical garlic, often as an unintended consequence of using garlic medicinally on the skin (585,4832,51226,51230,51252,51281,51377,51418,51468,51495,51536)(51558,51576,51577,88409,96006). A case of painful blisters on the soles of the feet of a 23-year-old Chinese female has been attributed to chemical burns caused by applying crushed raw garlic for 3 hours (51440). Topically, garlic may also cause hyperpigmentation, ulcers, necrotic lesions, facial flushing, and local irritation (4832,15030,51268,51269,108606). In one case report, applying crushed raw garlic to the palatal mucosa for several minutes to relieve mouth pain resulted in a chemical burn that produced a 3 cm necrotic ulcer in an adult female with trigeminal neuralgia (108606).

Gastrointestinal ...Orally, dehydrated garlic preparations or raw garlic may cause malodorous breath (51438,51444), body odor (732,1873,4784,4793,4795,4798,9201,10787,42692,49769)(51269,51316,51467,51602), abdominal pain or fullness, anorexia, diarrhea, constipation, flatulence, belching, heartburn, nausea, unpleasant taste, reflux, and bowel obstruction (1884,6457,6897,9201,49769,51269,51343,51380,51438,51442)(51450,51457,51466,51471,51474,51520,51593,51602,51623,88398)(88405,111766).
Large quantities of garlic may damage the gastrointestinal tract. In one case report, a patient taking garlic for hypertension reported odynophagia and retrosternal pain after taking garlic without any water the previous day. An esophageal lesion 3 cm in length was detected upon endoscopy. The symptoms resolved 3 days after starting a liquid diet and taking lansoprazole 30 mg twice daily and sucralfate four times daily (88389). One case of bowel obstruction was reported in a 66-year-old male who ingested an entire garlic bulb (51525). Esophageal perforation has been reported in at least 17 individuals who consumed entire garlic cloves. In one case the perforation led to mediastinitis and death (102672).
Garlic has also been associated with eosinophilic infiltration of the gastrointestinal tract. In one case report a 42-year-old female presented with symptoms of eosinophilic gastroenteritis, which included pollinosis, asthma, diarrhea, heart burn, peripheral eosinophilia, and urticaria. After stopping use of garlic and sesame, the patient improved (51441). In a case report of eosinophilic esophagitis, garlic was determined to be the causative agent in a patient with long-standing gastrointestinal symptoms. The patient had attempted to treat upper gastrointestinal symptoms as gastrointestinal reflux disease without success for many years. Skin prick testing showed a positive reaction to garlic, of which the patient noted frequent consumption. Marked symptom improvement was noted within 3 weeks of garlic avoidance (88393).
Intravenously, garlic 1 mg/kg of body weight daily diluted into 500 mL saline and administered over 4 hours has been reported to cause abdominal discomfort, vomiting, diarrhea, nausea, anorexia, flatulence, weight loss, and garlicky body odor (51462).
Clinical research suggests that patients with metabolic syndrome taking 1600 mg of powdered garlic by mouth daily for 3 months may experience improved intestinal transit time when compared with placebo, suggesting that garlic powder may reduce symptoms of constipation (110722).

Genitourinary ...Orally, garlic might cause dysuria or polyuria (51438,51450,51467).

Hematologic ...Oral use of dietary garlic or supplements containing garlic has caused platelet dysfunction, increased fibrinolytic activity, prolonged bleeding time, retrobulbar hemorrhage (bleeding behind the eye) postoperative bleeding, and spinal epidural hematoma (586,587,4801,4802,11325,51397,51473,51491,51532,51534)(51570,51584,51593,51594). Also, a case of kidney hematoma following extracorporeal shock-wave lithotripsy (SWL) has been reported in a patient with nephrolithiasis who took aged garlic (51630). A case of increased bleeding time that complicated epistaxis management has been reported in a patient taking garlic, aspirin, and milk thistle (51426).
Intravenously, garlic has been associated with the development of thrombophlebitis at the injection site (51462).

Immunologic ...There is a case report of an immediate sensitivity reaction to oral raw garlic, resulting in wheals, in a 31-year-old female. The patient did not react to cooked garlic, and skin prick tests showed allergy only to raw garlic (96015). Researchers note that at least some allergens in raw garlic are heat labile (88392,96012,96015). This suggests that consuming cooked rather than raw garlic may help avoid this reaction in patients allergic to raw garlic. However, different people react to different allergens in garlic. At least some of these allergens are heat stable (96012). While rare, garlic-induced anaphylaxis has been reported (88392,96012).
Topically, allergic contact dermatitis has been reported in case reports (51406,51498,51510,51519,51560).

Musculoskeletal ...Orally, garlic has been associated with individual cases of gout and low back pain (51474,51467), but it is not clear if these adverse events can be attributed to garlic.

Neurologic/CNS ...Orally, dizziness, insomnia, headaches, diaphoresis, fever, chills, somnolence, increased appetite, euphoria, and weight loss have been reported with garlic (15032,42692,51316,51467,51471,51520). In one case, the smell of garlic was identified as a trigger for migraines in a 32-year-old female. The subject reported fortification spectra along with visual spots for a few seconds followed by instantaneous biparietal, crushing level (10/10) headaches upon exposure to the scent of garlic or onion (88404).

Pulmonary/Respiratory ...Garlic exposure, most notably in occupational settings, may cause asthma and other symptoms such as sneezing, nasal obstruction, rhinorrhea, and sinusitis (40661,51218). A case of minor hemoptysis has been reported for one patient with cystic fibrosis following intake of garlic capsules orally once daily for 8 weeks (51438). A 77-year-old female developed pneumonia related to the intake of one whole black garlic clove daily. The cloves were prepared by heating a whole garlic bulb in a pot for one month. Symptoms included dyspnea and coughing, and test results were positive for lymphocyte-induced stimulation by black garlic and raw garlic. The patient required treatment with oral steroids and was told to avoid garlic (96011).

General ...Orally, horseradish is generally well tolerated when consumed in amounts commonly used with foods. But consuming large amounts of horseradish can cause various adverse effects.
Most Common Adverse Effects:
Orally: When consumed in large amounts, bloody vomiting, diarrhea, gastrointestinal upset.
Topically: Fresh horseradish can cause irritation or allergic reaction.
Serious Adverse Effects (Rare):
Orally: Transient vasovagal syncope.

Dermatologic ...Topically, skin contact with fresh horseradish can cause irritation (4,19) or allergic reaction (4).

Endocrine ...Orally, horseradish and other members of the cabbage and mustard family are associated with depressed thyroid function (4).

Gastrointestinal ...Orally, consuming large amounts of horseradish can cause gastrointestinal upset, bloody vomiting and diarrhea (2,6), and irritation of mucous membranes (2,4).

Genitourinary ...Orally, consuming large amounts of horseradish can cause irritation of the urinary tract (19).

Neurologic/CNS ...Orally, consuming large amounts of horseradish can cause vasovagal syncope in rare cases. At least two cases of vasovagal syncope associated with horseradish consumption have been reported. In one case, a 56-year-old male experienced a sharp burning sensation in his stomach followed by tachycardia, weakness, and excessive perspiration after consuming an oyster topped with an olive-sized dollop of fresh horseradish. He experienced vasovagal syncope within 5 minutes of horseradish ingestion but regained consciousness moments later, with few residual symptoms and no medical intervention required. Researchers theorize that the vapors from horseradish can irritate the gastric or respiratory tract mucosa triggering the vaso-vagal response. Horseradish-induced vasovagal syncope has also been referred to as Seder syncope due to the tradition of consuming bitter herbs, including horseradish, during the Jewish Passover holiday dinner. To reduce the potential for this reaction, researchers suggest that freshly prepared horseradish rest before consumption, allowing some of the active vapor ingredient, thought to be isothiocyanate, to evaporate before ingestion (111724).

General ...Orally, kale is generally well tolerated when consumed in amounts commonly found in foods. No adverse effects have been reported with medicinal use. However, a thorough evaluation of safety outcomes has not been conducted.

General ...Orally, iodine-reduced laminaria seems to be well tolerated, while other laminaria formulations may contain excess amounts of iodine, as well as arsenic.
Most Common Adverse Effects:
Intravaginally: Cervical bleeding and pelvic cramps.
Serious Adverse Effects (Rare):
Orally: Arsenic poisoning.
Intravaginally: Rupture of cervical wall, fetal hypoxia, and fetal death. Anaphylaxis in sensitive individuals.

Dermatologic ...Orally, laminaria has been linked to a report of induced or exacerbated acne (9555).

Endocrine ...Orally, laminaria can affect levels of certain thyroid hormones, and might cause hypothyroidism or hyperthyroidism, or exacerbate existing hyperthyroidism (9556,94046).

Genitourinary ...Intravaginally, laminaria used for cervical ripening can cause pelvic cramps and cervical bleeding (8945). Uterine contractions associated with laminaria use have been implicated in fetal hypoxia and subsequent intrauterine death (6). Use of endocervical laminaria tents has been associated with possible rupture of the cervical wall and subsequent neonatal and parental infection (6,8945).

Immunologic ...There are case reports of anaphylactic reactions to laminaria when used intravaginally as a cervical dilator. In at least one case, ventilation was required (102766).

Other ...Laminaria concentrates arsenic from the ocean. In one case, use of an oral laminaria supplement for several months resulted in symptoms of arsenic poisoning including headache, weakness, fatigue, worsening memory loss, rash, nail damage, diarrhea, and vomiting. Urinary arsenic levels were elevated (15588). The concentration of arsenic in laminaria may vary between different batches, and also depends upon the part of the world where it was harvested (645,10275,15588). The concentration of arsenic has been reported to be higher in preparations from Australia than from Great Britain (645,10275).

LIPASE

General ...No adverse effects have been reported in adults. However, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Gastrointestinal adverse effects, such as necrotizing enterocolitis, when recombinant human bile salt-stimulated lipase is used in premature infants.

Gastrointestinal ...Orally, when added to the formula or pasteurized breast milk consumed by premature infants, recombinant human bile salt-stimulated lipase (rhBSSL) can cause gastrointestinal adverse effects, including abdominal distension, flatulence, constipation, colic, abdominal pain, gastroenteritis, vomiting, regurgitation, and rectal bleeding (101940). Premature infants receiving rhBSSL also had a slightly higher rate of necrotizing enterocolitis (NEC) when compared with those receiving placebo. After review by a panel of experts, it was determined that the rate of confirmed or suspected NEC in infants consuming rhBSSL was 3.3%, compared with 0.5% in those receiving placebo. Although this rate of NEC is lower than the historical rate of occurrence in premature infants (11%), a possible increased risk for NEC cannot be ruled out (101940).

General ...Orally, oats are well tolerated.
Most Common Adverse Effects:
Orally: Abdominal distension, bloating, flatulence, and unpleasant taste.
Topically: Burning, contact dermatitis, itching, and redness.

Dermatologic ...Topically, oat-containing preparations can cause contact dermatitis (12515). Redness, burning, and itchiness have also been reported (103340).

Gastrointestinal ...When consumed orally, oats provide fiber. Increasing fiber in the diet can cause flatulence, bloating, abdominal distention, and unpleasant taste. To minimize side effects, doses should be slowly titrated to the desired level. These adverse effects usually subside with continued use (12514).
In patients who have difficulty chewing food, or those with conditions that decrease small bowel motility, oat bran may cause bezoars (concretions) and intestinal obstruction. Oats and oat bran are unlikely to cause obstruction without other causative factors (4979,4985).

General ...Orally, onion is well tolerated. Topically, onion is generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, heartburn.
Topically: Eczema, irritation.
Serious Adverse Effects (Rare):
All ROAs: Anaphylaxis in sensitive individuals.

Dermatologic ...Topically, frequent contact with onions can result in hand eczema, pemphigus, sensitization, and irritation (18,5004,51303,67066,67093).

Gastrointestinal ...The consumption of large quantities of onions or onion powder can cause stomach distress or heartburn (18,95155,104772). Stomach distress from onion powder appears to be transient (104772). In one case report, consumption of raw onions led to esophageal spasm (66841).

Immunologic ...Allergy to onion is rare, although there are reports of symptoms to both oral and topical exposure (41752,101743). In one case, oral exposure or the aroma of onions caused the sensation of throat closing in an allergic woman (88404). In a 35-year-old man, cooked onion ingestion triggered anaphylaxis (101742). In another case, the smell of onion was identified as a trigger for migraines in a 32-year-old female. Because the patient had a positive allergy skin test for onion, allergenic or immunogenic mechanisms were considered to be the origin of the migraines (88404).

Ocular/Otic ...Exposure to onion aroma can cause excessive tearing (67049).

General ...Orally, parsley seems to be well tolerated when used low to moderate doses. In rare cases, allergy to parsley has been reported (92869,92870). In large doses (i.e., 200 grams) parsley oil may cause significant adverse effects due to its potentially toxic constituents, apiole and myristicin (11). Adverse effects specifically associated with more than 10 grams of the constituent apiole include hemolytic anemia, thrombocytopenia purpura, nephrosis, hepatic dysfunction, and kidney irritation (4). Adverse effects specifically associated with the constituent myristicin include giddiness, deafness, hallucinations, hypotension, bradycardia, paralysis, and fatty degeneration of the liver and kidneys (4). Parsley oil can also cause contact photodermatitis with sun exposure (4).
Topically, parsley can cause contact photodermatitis (4).

Cardiovascular ...Parsley contains the potentially toxic constituent, myristicin, which can cause significant adverse effects at high doses (11). Adverse effects specifically associated with myristicin include hypotension and bradycardia (4).

Dermatologic ...Orally, parsley oil can cause contact photodermatitis with sun exposure (4).
Topically, parsley can cause contact photodermatitis (4).

Hematologic ...Parsley contains the potentially toxic constituent apiole, which can cause significant adverse effects at high doses (11). Adverse effects specifically associated with more than 10 grams of the constituent apiole include hemolytic anemia and thrombocytopenia purpura (4).

Hepatic ...Parsley contains the potentially toxic constituents, apiole and myristicin, which can cause significant adverse effects at high doses (11). Adverse effects specifically associated with more than 10 grams of the constituent apiole include hepatic dysfunction (4). Adverse effects specifically associated with the constituent myristicin include fatty degeneration of the liver (4).

Immunologic ...A case of anaphylaxis involving severe angioedema leading to unconsciousness has been reported in a woman who consumed parsley 45 minutes prior to symptoms. The patient responded to epinephrine, antihistamines, intravenous fluids, oxygen therapy, and 1 mg/kg methylprednisolone. The woman had consumed one cup of chopped parsley nearly every day for several years, but upon skin testing, the patient tested positive to parsley (92869). There is also a report of lip angioedema after consumption of raw parsley. The patient had anaphylaxis to raw arugula, and reported itchy red lesions after contact with the leaves of either raw parsley or arugula. The patient had positive skin prick tests to both plants. The reaction may have been due to oral allergy syndrome, as the patient could tolerate cooked arugula and parsley, but not raw (92870).

Ocular/Otic ...Parsley contains the potentially toxic constituent, myristicin, which can cause significant adverse effects at high doses (11). An adverse effect specifically associated with the constituent myristicin includes deafness (4).

Psychiatric ...Parsley contains the potentially toxic constituent, myristicin, which can cause significant adverse effects at high doses (11). Adverse effects specifically associated with the constituent myristicin include giddiness and hallucinations (4).

Renal ...Parsley contains the potentially toxic constituents, apiole and myristicin, which can cause significant adverse effects at high doses (11). Adverse effects specifically associated with more than 10 grams of the constituent apiole include nephrosis and kidney irritation (4). Adverse effects specifically associated with the constituent myristicin include fatty degeneration of the kidneys (4).

PHYTASE

General ...Orally, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted. Workplace immunological responses to airborne powdered phytase have been reported (101901,101908,101909,101910).

Immunologic ...There are numerous reports of immunologic responses to airborne powdered phytase in the animal-feed industry (101901,101908,101909,101910). Examples of reactions include allergic occupational asthma and hypersensitivity pneumonitis (101901,101908). In one case report of a 43-year-old male, hypersensitivity pneumonitis related to phytase was diagnosed following a 6-month history of coughing, shortness of breath, fever, and dyspnea (101908). In an analysis of 53 people occupationally exposed to phytase, 28% had IgE antibodies and 45% had IgG antibodies specific to phytase. Symptoms included dyspnea, rhinitis, and eye and skin reactions (101909). In another analysis of patients with IgE-mediated occupational respiratory allergy, wheezing, chest tightness, shortness of breath, cough, and asthmatic symptoms were reported (101910).

General ...Orally, proteolytic enzymes are generally well tolerated. See specific monographs for detailed safety information related to individual proteolytic enzymes.
Most Common Adverse Effects:
Orally: Gastrointestinal upset.
Serious Adverse Effects (Rare):
Topically: Allergic reactions.

Gastrointestinal ...Orally, some patients taking proteolytic enzymes may have gastrointestinal complaints (101517).

Immunologic ...Proteolytic enzymes are commonly found in laundry detergents and pre-spotter products. Rarely, protease specific IgE positive tests possibly related to these products have occurred. Exposure may be airborne or topical (102705). In addition, in case reports, occupational exposure to the airborne proteolytic enzyme pepsin has resulted in allergic rhinoconjunctivitis or asthma (102706,102707).

General ...Orally, pumpkin products are generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal discomfort, diarrhea, nausea, and vomiting.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis.

Dermatologic ...There are two case reports of adult females developing substantial transient hair loss 1-3 weeks after consumption of a meal containing either bitter-tasting pumpkin or undefined squash. This adverse effect was attributed to a high concentration of cucurbitacin, which is commonly found in wild pumpkins (104535).

Gastrointestinal ...Orally, pumpkin seed oil has been reported to cause mild abdominal discomfort in clinical trials (5093,92378). There are also two case reports of adults developing severe nausea, vomiting, and diarrhea following consumption of a meal containing either bitter-tasting pumpkin or undefined squash. These adverse effects were attributed to a high concentration of cucurbitacin, which is commonly found in wild pumpkins (104535).

Immunologic ...Orally, pumpkin seed oil and pumpkin pulp have been reported to cause anaphylactic reactions in children and adults. A case review highlights 4 cases of anaphylaxis in children (3 from pumpkin pulp, 1 from pumpkin seeds), and 7 cases in adults (1 from pumpkin flesh, 6 from pumpkin seeds). Symptoms of anaphylaxis include urticaria, angioedema of the lips or face, dyspnea, dysphagia, and oropharyngeal itching and swelling. A case report describes a 2-year-old male presenting with urticaria, swollen lips, and increased dyspnea 10 minutes after ingesting pumpkin seeds. The patient was found to have elevated allergen-specific immunoglobulin E (IgE) and a positive skin-prick test for pumpkin seeds. Symptoms resolved after treatment with epinephrine, systemic glucocorticoids, salbuterol, and antihistamines (107843).
There may also be concern for allergic reaction due to inhalation or topical exposure. One case report describes an 8-year-old child developing anaphylaxis while carving a pumpkin; another highlights that inhalation of pumpkin seed flour may have potentiated anaphylaxis in 3 individuals following the ingestion of pumpkin seeds (107843). Further research is necessary to assess the relationship between anaphylaxis and route of administration.

General ...Orally, selenium is generally well-tolerated when used in doses that do not exceed the tolerable upper intake level (UL) of 400 mcg daily. Intravenously, selenium is generally well-tolerated.
Most Common Adverse Effects:
Orally: Gastric discomfort, headache, and rash. Excessive amounts can cause alopecia, dermatitis, fatigue, nail changes, nausea and vomiting, and weight loss.
Serious Adverse Effects (Rare):
Orally: Excessive ingestion has led to cases of multi-organ failure and death.

Dermatologic ...Excess selenium can produce selenosis in humans, affecting liver, skin, nails, and hair (74304,74326,74397,74495,90360) as well as dermatitis (74304). Results from the Nutritional Prevention of Cancer Trial conducted among individuals at high risk of nonmelanoma skin cancer demonstrate that selenium supplementation is ineffective at preventing basal cell carcinoma and that it increases the risk of squamous cell carcinoma and total nonmelanoma skin cancer (10687). Mild skin rash has been reported in patients taking up to 200 mcg of selenium daily for up to 12 months (97943).

Endocrine ...Multiple clinical studies have found an association between increased intake of selenium, either in the diet or as a supplement, and the risk for type 2 diabetes (97091,99661). One meta-analysis shows that a selenium plasma level of 90 mcg/L or 140 mcg/L is associated with a 50% or 260% increased risk for developing type 2 diabetes, respectively, when compared with plasma levels below 90 mcg/L. Additionally, consuming selenium in amounts exceeding the recommended dietary allowance (RDA) is associated with an increased risk of developing diabetes when compared with consuming less than the RDA daily. Also, taking selenium 200 mcg daily as a supplement is associated with an 11% increased risk for diabetes when compared with a placebo supplement (99661).
Hypothyroidism, secondary to iodine deficiency, has been reported as a result of selenium intravenous administration (14563,14565). One large human clinical trial suggested a possible increased risk of type 2 diabetes mellitus in the selenium group (16707).

Gastrointestinal ...In human research, nausea, vomiting, and liver dysfunction has been reported as a result of high selenium exposure (74439,74376). Mild gastric discomfort has been reported in patients taking up to 200 mcg of selenium daily for up to 12 months (97943).

Genitourinary ...The effect of selenium supplementation on semen parameters is unclear. In human research, selenium supplementation may reduce sperm motility (9729); however, follow-up research reported no effect on sperm motility or any other semen quality parameter (74441).

Neurologic/CNS ...Chronic exposure to organic and inorganic selenium may cause neurotoxicity, particularly motor neuron degeneration, leading to an increased risk of amyotrophic lateral sclerosis (ALS) (74304). Mild headache has been reported in patients taking up to 200 mcg of selenium daily for up to 12 months (97943).

General ...Orally, spinach is well tolerated when consumed as a food.
Serious Adverse Effects (Rare):
Orally: In infants under 4 months of age, methemoglobinemia has been reported.
All routes of administration: Allergies in sensitive individuals.

Dermatologic ...Topically, contact dermatitis has been reported from spinach in a 54-year-old female farmer (41757).

Gastrointestinal ...Bagged spinach has been linked to Escherichia coli outbreaks, sometimes causing severe gastrointestinal symptoms and even death (75846,75847,75849,75851,96858).

Hematologic ...Orally, spinach ingestion by infants under 4 months of age can cause methemoglobinemia, due to its high nitrate content (75802,75858,75860,75861,75862).

Immunologic ...Orally, topically, and via inhalation, spinach has been reported to cause allergic reactions in sensitive individuals (75870,96859).

Pulmonary/Respiratory ...Lung inflammation associated with allergic alveolitis has been reported after inhalation of spinach powder (75871). The powder has also been reported to induce occupational asthma in a spinach factory worker (75833).

General ...Orally, tomato leaves and ripe or unripe tomato fruit are well tolerated in typical food amounts. Tomato extracts also seem to be well tolerated. Tomatine, a glycoalkaloid found in tomato leaves and unripe green tomatoes, can cause serious side effects when consumed in excessive amounts.
Serious Adverse Effects (Rare):
Orally: Bradycardia, diarrhea, respiratory disturbances, spasms, vomiting, and death with excessive consumption of tomatine, a glycoalkaloid found in tomato leaves and unripe green tomatoes.

Cardiovascular ...Orally, the glycoalkaloid tomatine in tomato leaf or green tomatoes can cause bradycardia when consumed in excessive amounts (18,102957).

Gastrointestinal ...Orally, the glycoalkaloid tomatine in tomato leaf or green tomatoes can cause severe mucous membrane irritation, vomiting, diarrhea, and colic when consumed in excessive amounts (18,102957).

Immunologic ...In a case report, a 31-year-old female working in the supermarket developed an airborne allergy to tomato stem proteins with symptoms of severe rhinoconjunctivitis. This woman did not have a food allergy to tomato fruit (102467).

Neurologic/CNS ...Orally, the glycoalkaloid tomatine in tomato leaf or green tomatoes can cause dizziness, stupor, headache, and mild spasms when consumed in excessive amounts (18,102957).

Pulmonary/Respiratory ...Orally, the glycoalkaloid tomatine in tomato leaf or green tomatoes can cause respiratory disturbances when consumed in excessive amounts. In severe cases, death by respiratory failure might occur (18,102957).

VITAMIN A

General ...Orally, vitamin A is generally well-tolerated at doses below the tolerable upper intake level (UL).
Serious Adverse Effects (Rare):
Orally: In very high doses, vitamin A can cause pseudotumor cerebri, pain, liver toxicity, coma, and even death.

Dermatologic ...Chronic oral use of large amounts of vitamin A causes symptoms of vitamin A toxicity including dry skin and lips; cracking, scaling, and itchy skin; skin redness and rash; hyperpigmentation; shiny skin, and massive skin peeling (7135,95051). Hypervitaminosis A can cause brittle nails, cheilitis, gingivitis, and hair loss (15,95051). Adverse effects from a single ingestion of a large dose of vitamin A is more common in young children than adults (15). In children, approximately 25,000 IU/kg can cause skin redness and generalized peeling of the skin a few days later and may last for several weeks (15).

Gastrointestinal ...There is some evidence that oral vitamin A supplementation might increase the risk of diarrhea in children. Although vitamin A can prevent diarrhea and reduce mortality in malnourished children, doses as low as 10,000 IU weekly for 40 weeks have been associated with diarrhea in well-nourished children (319). Diarrhea (82326,82389), nausea (7135,100329), abdominal pain (95051), abdominal fullness (100329), and vomiting (7135,82559,95051,95055,109755) have been reported following use of large doses of oral vitamin A. Adverse effects from a single ingestion of a large dose of vitamin A is more common in young children than adults (15). In children, approximately 25,000 IU/kg can cause vomiting and diarrhea (15). Chronic use of large amounts of vitamin A causes symptoms of vitamin A toxicity including anorexia, abdominal discomfort, and nausea and vomiting (7135).

Genitourinary ...Hypervitaminosis A can cause reduced menstrual flow (15). Intravaginally, all-trans retinoic acid can cause vaginal discharge, itching, irritation, and burning (9199).

Hematologic ...Hypervitaminosis A can cause spider angiomas, anemia, leukopenia, leukocytosis, and thrombocytopenia (15,95051).

Hepatic ...Since the liver is the main storage site for vitamin A, hypervitaminosis A can cause hepatotoxicity, with elevated liver enzymes such as alanine aminotransferase (ALT, formerly SGPT) and aspartate aminotransferase (AST, formerly SGOT), as well as fibrosis, cirrhosis, hepatomegaly, portal hypertension, and death (6377,7135,95051).

Musculoskeletal ...Vitamin A can increase the risk for osteoporosis and fractures. Observational research has found that chronic, high intake of vitamin A 10,000 IU or more per day is associated with an increased risk of osteoporosis and hip fracture in postmenopausal adults, as well as overall risk of fracture in middle-aged males (7712,7713,9190). A meta-analysis of these and other large observational studies shows that high dietary intake of vitamin A or retinol is associated with a 23% to 29% greater risk of hip fracture when compared with low dietary intake (107294). High serum levels of vitamin A as retinol also increase the risk of fracture in males. Males with high serum retinol levels are seven times more likely to fracture a hip than those with lower serum retinol levels (9190). Vitamin A damage to bone can occur subclinically, without signs or symptoms of hypervitaminosis A. Some researchers are concerned that consumption of vitamin A fortified foods such as margarine and low-fat dairy products in addition to vitamin A or multivitamin supplements might cause excessive serum retinol levels. Older people have higher levels of vitamin A and might be at increased risk for vitamin A-induced osteoporosis.
Vitamin A's effects on bone resorption could lead to hypercalcemia (95051).
Hypervitaminosis can cause slow growth, premature epiphyseal closure, painful hyperostosis of the long bones, general joint pain, osteosclerosis, muscle pain, and calcium loss from the bones (15,95051). One child experienced severe bone pain after taking vitamin A 600,000 IU daily for more than 3 months (95051). Vitamin A was discontinued and symptoms lessened over a period of 2 weeks. The patient made a full recovery 2 months later.

Neurologic/CNS ...Orally, adverse effects from a single large dose of vitamin A are more common in young children than adults (15). Headache, increased cerebrospinal fluid pressure, vertigo, and blurred vision have been reported following an acute oral dose of vitamin A 500,000 IU (7135). In children, approximately 25,000 IU/kg can cause headache, irritability, drowsiness, dizziness, delirium, and coma (15). Chronic use of large amounts of vitamin A causes symptoms of vitamin A toxicity including fatigue, malaise, lethargy, and irritability (7135).
There are reports of bulging of the anterior fontanelle associated with an acute high oral dose of vitamin A in infants (7135,90784,95053,95054). In children, approximately 25,000 IU/kg can cause increased intracranial pressure with bulging fontanelles in infants (15). Also, muscular incoordination has been reported following short-term high doses of vitamin A (7135).
A case of intracranial hypertension involving diffuse headaches and brief loss of vision has been reported secondary to topical use of vitamin A. The patient was using over-the-counter vitamin A preparations twice daily including Avotin 0.05% cream, Retin-A gel 0.01%, and Isotrexin gel containing isotretinoin 0.05% and erythromycin 2%, for treatment of facial acne. Upon exam, the patient was noted to have bilateral optic disc edema. The patient discontinued use of topical vitamin A products. Two months later, the patient reported decreased headaches and an improvement in bilateral optic disc edema was seen (95056).

Ocular/Otic ...In children, oral vitamin A approximately 25,000 IU/kg can cause swelling of the optic disk, bulging eyeballs, and visual disturbances (15). Adverse effects from a single ingestion of a large dose of vitamin A are more common in young children than adults (15).

Oncologic ...There is concern that high intake of vitamin A might increase some forms of cancer. Population research suggests high vitamin A intake might increase the risk of gastric carcinoma (9194).

Psychiatric ...Chronic oral use of large amounts of vitamin A causes symptoms of vitamin A toxicity, which can include symptoms that mimic severe depression or schizophrenic disorder (7135).

Pulmonary/Respiratory ...There is some evidence that oral vitamin A supplementation might increase the risk of pneumonia and diarrhea in children. Although vitamin A can prevent diarrhea and reduce mortality in malnourished children, doses as low as 10,000 IU weekly for 40 weeks have been associated with pneumonia and diarrhea in well-nourished children (319). In preschool children, high-dose vitamin A also increases the risk of respiratory infection (82288).

Other ...Chronic use of large amounts of vitamin A (>25,000 IU daily for more than 6 years or 100,000 IU daily for more than 6 months) can cause symptoms of vitamin A toxicity including mild fever and excessive sweating (7135). High intakes of vitamin A may result in a failure to gain weight normally in children and weight loss in adults (15).

VITAMIN E

General ...Orally and topically, vitamin E is generally well-tolerated.
Serious Adverse Effects (Rare):
Orally: Bleeding, hemorrhagic stroke, cardiovascular complications.
Inhaled: Vitamin E acetate is thought to be responsible for e-cigarette, or vaping, product-use associated lung injury (EVALI).

Cardiovascular ...Some evidence suggests that taking vitamin E supplements, especially greater than or equal to 400 IU taken by mouth daily for over one year, might also increase the risk of mortality in non-healthy patients (12212,13036,15305,16709,83339). A population study shows that vitamin E use is associated with a significantly increased risk of mortality in people with a history of severe cardiovascular disease such as stroke or myocardial infarction (16709). In an analysis of clinical trials, patients who took either all-rac-alpha-tocopherol (synthetic vitamin E) or RRR-alpha-tocopherol (natural vitamin E) in doses of 400 IU/day or higher had an increased risk of mortality from all causes. The risk of mortality seems to increase when higher doses are used (12212). A large-scale study also suggests that patients with diabetes or cardiovascular disease who take RRR-alpha-tocopherol (natural vitamin E) 400 IU daily have an increased risk of heart failure and heart failure-related hospitalization (13036). However, in another large scale study, taking 600 IU vitamin E every other day for 10 years did not increase the risk of heart failure in healthy females over 45 years of age (90068). There is speculation that high-dose vitamin E might disrupt the normal antioxidant balance and result in pro-oxidant rather than antioxidant effects.
There is some evidence that vitamin E in combination with simvastatin (Zocor), niacin, selenium, vitamin C, and beta-carotene might lower high density lipoprotein-2 (HDL-2) by 15%. HDL-2 is considered to be the most cardioprotective component of HDL (7388). However, vitamin E and a statin alone don't seem to negatively affect HDL (11286,11287). In addition, vitamin E has been associated with increased triglycerides (85215). Although only certain isomers of vitamin E are included for determination of dietary requirements, all isomers are considered for determining safe intake levels. All the isomers are thought to potentially contribute to toxicity.

Dermatologic ...Topically, vitamin E has been associated with contact dermatitis, inflammatory reactions, and eczematous lesions (11998,85066,85285). Dermatitis, often associated with moisturizers containing vitamin E, has a scattered generalized distribution, is more common on the face than the hands, and is more common in females with a history of atopic dermatitis. In a retrospective analysis of results of patch tests for DL-alpha-tocopherol sensitivity, 0.9% of patients had a definite positive reaction, while over 50% had a weakly positive, non-vesicular erythematous reaction (107869).
Orally, vitamin E has been associated with pruritus in one clinical trial (34596).
Subcutaneously, vitamin E has been associated with reports of lipogranuloma (85188,112331). In one case, subcutaneous injection of a specific supplement (1Super Extenze), containing mineral oil and tocopherol acetate, into the penile tissue resulted in penile disfigurement due to sclerosing lipogranuloma (85188). In another case, a 50-year-old Iranian female presented with lipogranuloma of the face, characterized by severe facial erythema, edema, and tenderness, 3 months after receiving subcutaneous injections of vitamin E to the cheeks for "facial rejuvenation." The patient had noticed initial symptoms within 3 days, and her symptoms progressively worsened over time (112331).

Gastrointestinal ...Orally, vitamin E supplementation has been associated with abdominal pain, nausea, diarrhea, or flu-like symptoms (85040,85323). Intravenously, large doses of vitamin E in premature infants are associated with an increased risk of necrotizing enterocolitis and sepsis (85083,85231).

Genitourinary ...There is contradictory evidence about the effect of vitamin E on prostate cancer risk. One large-scale population study shows that males who take a multivitamin more than 7 times per week and who also take a separate vitamin E supplement have a significantly increased risk of developing prostate cancer (15607). In a large-scale clinical trial (The SELECT trial) in males over the age of 50 years, taking all-rac-alpha-tocopherol (synthetic vitamin E) 400 IU daily increased the risk of developing prostate cancer by 17% when compared with placebo. However, the difference in prostate cancer risk between vitamin E and placebo became significant only 3 years after patients stopped taking supplementation and were followed in an unblinded fashion. Interestingly, patients taking vitamin E plus selenium did not have a significantly increased risk of prostate cancer (17688).

Hematologic ...High doses of vitamin E might increase the risk of bleeding due to antagonism of vitamin K-dependent clotting factors and platelet aggregation. Patients with vitamin K deficiencies or taking anticoagulant or antiplatelet drugs are at a greater risk for bleeding (4098,4844,11999,34596,34538,34626,34594,112162).

Neurologic/CNS ...There is concern that vitamin E might increase the risk of hemorrhagic stroke (16708,34594,34596,108641). In one clinical study, there was a higher incidence of hemorrhagic stroke in male smokers taking all-rac-alpha-tocopherol (synthetic vitamin E) for 5-8 years compared to those not taking vitamin E (3949). Other studies lasting from 1.4-4.5 years and using either all-rac-alpha-tocopherol (synthetic vitamin E) or RRR-alpha-tocopherol (natural vitamin E) showed no significantly increased risk for stroke (2307,3896,3936). A meta-analysis of studies shows that vitamin E in doses of 300-800 IU daily, including both natural and synthetic forms, does not significantly affect total stroke risk. However, it significantly increases the risk of hemorrhagic stroke by 22%. This means that there will be one additional hemorrhagic stroke for every 1250 patients taking vitamin E. In contrast to this finding, the analysis also found that vitamin E significantly reduces the risk of ischemic stroke by 10%. This means that one ischemic stroke will be prevented for every 476 patients taking vitamin E (14621). In patients with moderately severe Alzheimer disease, taking vitamin E 2000 IU for 2 years has been associated with a modest, but significant, increase in falls and episodes of syncope when compared to placebo (4635).

Pulmonary/Respiratory ...When inhaled, vitamin E acetate is thought to play a role in the development of e-cigarette, or vaping, product-use associated lung injury (EVALI). Although a causal link has not yet been determined, in two case series, vitamin E acetate has been found in most bronchoalveolar lavage samples taken from the primary site of lung injury in patients with EVALI, whereas no vitamin E was found in healthy control samples. Other ingredients, including THC or nicotine, were also commonly found in samples. However, priority toxicants including medium chain triglyceride (MCT) oil, plant oil, petroleum distillate, or terpenes, were undetectable in almost all samples. EVALI has resulted in death in some patients (101062,102970).

Other ...In an analysis of 3 trials, taking vitamin E 400 IU with vitamin C 1000 mg daily for 14-22 weeks during gestation appears to increase the risk of gestational hypertension by 30% compared to placebo in patients at risk of pre-eclampsia. However, the risk of pre-eclampsia itself was not increased (83450).

WHEATGRASS (organic Wheat Grass fine ground powder)

General ...Orally, wheatgrass is generally well tolerated. It can cause nausea, anorexia, and constipation (11165).

Gastrointestinal ...Orally, wheatgrass may cause nausea, anorexia, and constipation (11165).

Immunologic ...Wheat can cause allergic reactions in sensitive individuals. Due to the prevalence of this allergy in the general population, wheat and wheat products, such as wheatgrass, are classified as major food allergens in the United States (105410).

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