Enzymes [Discontinued] by New Earth

POSSIBLY EFFECTIVE

• 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).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• 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.

(Read more about BLUE-GREEN ALGAE)

POSSIBLY EFFECTIVE

• Atopic dermatitis (eczema). In infants at risk for atopy, providing syrup or formula containing GOS along with probiotics or fructo-oligosaccharides may reduce the risk of developing atopic dermatitis. Details: One large clinical trial in infants at high risk for allergies shows that feeding 20 drops of syrup containing GOS 0.8 grams, in combination with one opened capsule of probiotic bacteria, daily for 6 months reduces the incidence of dermatitis and atopic dermatitis by the age of 2 years when compared with placebo (26707). It is unclear if these findings are due to GOS, probiotics, or the combination, especially since mothers in the treatment group also took probiotics for 2-4 weeks before delivery. Also, a small clinical trial in newborns at risk for atopic disease shows that feeding a formula containing a combination of GOS and fructo-oligosaccharides 8 grams/L as often as necessary for 6 months reduces the risk, but not severity, of developing atopic dermatitis when compared with placebo formula (26708). At 2 years of age, the infants given this formula were half as likely to have developed atopic dermatitis (99223). However, in one study in healthy formula-fed infants, formula containing 4 grams/L of GOS and polydextrose (1:1 ratio) given as often as necessary for approximately 4 months increased the potential of developing atopic dermatitis as an adverse effect by up to 11% when compared with control formula (26709).
• Colic. Providing formula containing GOS and other ingredients may reduce the duration or frequency of crying episodes in infants with colic. Details: One clinical trial in infants with colic shows that feeding a formula containing 8 grams/L of a prebiotic mixture of GOS 90% and fructo-oligosaccharides 10% as often as necessary for 14 days reduces the number of colic episodes when compared with a control formula plus simethicone 6 mg/kg twice daily (26710). Another clinical trial in healthy infants 14-35 days of age shows that feeding a cow's milk-based formula containing 4 grams/L of a prebiotic blend of GOS and polydextrose (1:1 ratio) until around 4 months of age leads to faster normalization of daytime sleep patterns when compared with cow's milk-based formula alone. Episodes of crying were also shorter after 2 months, but not 4 months, of supplementation (106527). It is unclear if the findings from this study in healthy infants can be generalized to those with colic.
• Lactose intolerance. Oral GOS may improve some symptoms of lactose intolerance and allow for increased consumption of lactose-containing products, even after discontinuing GOS. Details: Although a small clinical study found no effect with the use of GOS (99224), one large clinical study in patients with lactose intolerance shows that taking GOS titrated up to 7.5-10 grams twice daily for 30 days improves overall symptoms of lactose intolerance, and in particular cramping and bloating, when compared with placebo (106526). Patients in these studies were asked to avoid lactose-containing products during the treatment period, so the effect of GOS on symptoms in patients actively consuming lactose products is unclear. After the study period, patients were asked to reintroduce lactose products into their diets. Those that had been taking GOS in both studies reported increased milk intake and fewer symptoms when compared with those previously treated with placebo, suggesting that the effects of GOS continue after discontinuation (99224,106526).

POSSIBLY INEFFECTIVE

• Allergic rhinitis (hay fever). Supplementation with oral GOS during the first 6 months of life may not prevent the development of allergic rhinitis in infants at risk for allergies. Details: One large clinical trial in infants at risk for allergies shows that feeding 20 drops of syrup containing GOS 0.8 grams, in combination with one opened capsule of probiotic bacteria, daily for 6 months does not reduce the risk of developing allergic rhinitis by the age of 2 years when compared with placebo (26707).
• Food allergies. Supplementation with oral GOS during the first 6-12 months of life may not prevent the development of food allergies at 1 or 2 years of age. Details: One large clinical trial in infants at risk for allergies shows that feeding 20 drops of syrup containing GOS 0.8 grams, in combination with one opened capsule of probiotic bacteria, daily for 6 months does not reduce the risk of developing food allergies by the age of 2 years when compared with placebo (26707). Another large clinical study in healthy, full-term infants shows that feeding a formula containing GOS 4.4-5 grams/L from 8 weeks of age until 12 months of age does not reduce the incidence of allergic sensitization to foods, based on skin prick testing, when compared with placebo (99218).
• Upper respiratory tract infection (URTI). Large studies suggest that oral GOS do not prevent the development of URTIs in healthy infants or young adults. It is unclear if GOS are beneficial for the prevention of URTIs in premature infants. Details: A large clinical study in healthy, term infants shows that feeding a formula containing GOS 4.4-5 grams/L from before 8 weeks of age until 12 months of age does not reduce the incidence of URTIs (99218). Also, a large clinical trial in healthy university students going through exam-related stress shows that taking GOS (Purimmune, GTC Nutrition) 2.5 or 5 grams daily for 8 weeks does not reduce the total number of cold or flu symptoms when compared with placebo (99221). GOS, in combination with polydextrose, has been evaluated in premature infants. A small clinical trial shows that feeding a 1:1 combination of these at a dose of 600-1200 mg daily during the first 60 days of life reduces the incidence of URTIs, including the common cold, when compared with placebo. However, this prebiotic combination does not seem to reduce the duration or severity of respiratory tract infections that do occur (99211). It is unclear if any effects are due to GOS, polydextrose, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. It is unclear if oral GOS are beneficial in patients with anxiety. Details: One small clinical study in healthy females 18-25 years of age shows that taking GOS 5.5 grams daily for 4 weeks does not improve anxiety scores overall or in subgroups of individuals reporting high or low baseline levels of anxiety when compared with placebo (106640).
• Asthma. It is unclear if GOS, alone or in combination with fructo-oligosaccharides, are beneficial for preventing the development of asthma or recurrent wheeze in infants at risk for allergies. Details: One large clinical study in infants at risk for allergies shows that feeding 20 drops of syrup containing GOS 0.8 grams, in combination with one opened capsule of probiotic bacteria, daily for 6 months does not reduce the risk of developing atopic disease, including asthma, by the age of 2 years when compared with placebo (26707). However, another large clinical study in newborns at risk for atopic disease shows that feeding a formula containing a combination of GOS and fructo-oligosaccharides 8 grams/L as often as necessary for 6 months reduces the risk of developing recurrent wheezing, a risk factor for asthma, by 2 years of age when compared with placebo. Approximately 8% of infants given GOS formula developed recurrent wheeze, compared to about 21% of those given placebo formula (99223). These discrepant findings may be due to differences in measured outcomes, as well as the doses and products studied.
• Colorectal cancer. Although there has been interest in using oral GOS for the prevention of colorectal cancer, there is insufficient reliable information about the clinical effects of GOS for this purpose.
• Constipation. It is unclear if oral GOS, when taken with water or added to yogurt, are beneficial in patients with constipation. Details: Preliminary clinical research in adults with constipation shows that taking a specific GOS product (Biotis GOS, Friesland Campina) orally as 5.5-11 grams daily for three weeks does not increase stool frequency when compared with placebo (107730). Similarly, one very small clinical study in elderly females with constipation shows that consuming yogurt containing a specific syrup (Elix'or, Borculo Domo Ingredients) providing GOS 4.5 grams twice daily for 2 weeks does not improve defecation frequency, laxative use, or ease of defecation when compared with placebo (26706). Another small clinical study in elderly patients with mild constipation shows that consuming yogurt containing GOS 12 grams, prunes 12 grams, and linseed 6 grams daily for 3 weeks increases the frequency and ease of defecation and improves relief when compared with a traditional yogurt in elderly patients with mild constipation (21191). However, it is unclear if these findings are due to GOS, other ingredients, _or the combination.
• Depression. It is unclear if oral GOS are beneficial in patients with depression. Details: One small clinical trial in patients with major depressive disorder shows that taking GOS 5 grams daily for 8 weeks does not improve symptoms of depression when compared with placebo, and appears to be less effective when compared with a probiotic supplement containing Lactobacillus helveticus and Bifidobacterium longum (102506).
• Diarrhea. Although there has been interest in using oral GOS for the prevention and treatment of diarrhea, including travelers' diarrhea, there is insufficient reliable information about the clinical effects of GOS for this purpose.
• Insomnia. Oral GOS have only been evaluated in combination with other ingredients; their effect when used alone is unclear. Details: One small crossover trial in adults with sleep disturbances shows that taking a combination product containing GOS 5.2 grams, whey protein 9.5 grams, large neutral amino acids 3.4 grams, and other vitamins and minerals one hour before bed nightly for 3 weeks does not improve sleep quality when compared with a control product containing no GOS and smaller amounts of protein, amino acids, vitamins, and minerals (106528).
• Iron deficiency anemia. GOS increases the absorption and tolerability of iron supplements, and may therefore be beneficial in patients with iron deficiency anemia. Details: Preliminary clinical research shows that taking GOS with iron supplements increases the absorption and tolerability of iron (102509,102510,107729). One small clinical trial in adult females shows that taking GOS 15 grams orally as a single dose increases the fractional iron absorption from oral ferrous sulfate, containing 104 mg iron, by 45% when compared with control (107729). Other clinical research in young, iron-deficient females, shows that giving GOS 963 mg/kg in addition to ferrous sulfate 30 ppm, increases mean hemoglobin, hematocrit, red blood cell count, mean corpuscular volume, serum iron, serum transferrin, and total iron binding capacity when compared with ferrous sulfate alone (110599).
• Irritable bowel syndrome (IBS). It is unclear if oral GOS are beneficial in patients with IBS. Details: One small clinical trial in patients with IBS shows that taking GOS 1.4 grams daily while following a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) for 4 weeks increases the odds of adequate IBS symptom relief by 4.6-fold when compared with placebo plus a sham diet. However, no difference in rate of adequate symptom relief was reported when GOS plus the low FODMAP diet were compared with placebo plus the low FODMAP diet, suggesting that any benefits may have been due to the diet (106525).
• Metabolic syndrome. It is unclear if oral GOS are beneficial in patients with metabolic syndrome. Details: A small clinical study in overweight patients with metabolic syndrome shows that taking GOS 5.5 grams daily for 12 weeks does not improve most measures of metabolic syndrome when compared with placebo. Although levels of total cholesterol, triglycerides, and insulin were reduced by a small amount, these changes were not clinically meaningful (99219).
• Neonatal jaundice. It is unclear if oral GOS are beneficial for the treatment of neonatal jaundice. Details: A small clinical study in healthy infants with mild hyperbilirubinemia shows that providing a formula containing a combination of GOS and fructo-oligosaccharides 8 grams/L as often as necessary for 28 days reduces levels of bilirubin within 72 hours when compared with those given placebo formula. Whether GOS can reduce bilirubin levels in infants with very high levels of bilirubin is unknown, as these infants were excluded from this study (99222).
• Obesity. It is unclear if oral GOS improves weight loss in overweight or obese adults. Details: A small clinical study in overweight adults shows that taking GOS 6 grams, 12 grams, or 18 grams daily in oolong tea for 2 weeks has a small effect on appetite and weight loss when compared with oolong tea alone. Weight loss of 0.1-0.2 kg occurred over the study period, compared with no change in those taking oolong tea alone (99217).
• Osteoporosis. Although there has been interest in using oral GOS for osteoporosis, there is insufficient reliable information about the clinical effects of GOS for this purpose.
• Prematurity. It is unclear if oral GOS are beneficial for improving cognitive or motor development in premature infants. Details: A small clinical study in premature infants shows that adding a combination of GOS, fructo-oligosaccharides, and pectin acidic oligosaccharides up to 1.5 grams/kg daily to breast milk or formula for 30 days after birth does not improve cognitive or motor development outcomes at the age of 2 years when compared with placebo (99216).
• Ulcerative colitis. It is unclear if oral GOS are beneficial in patients with ulcerative colitis. Details: Preliminary clinical research in adults with ulcerative colitis shows that taking a specific GOS product (Bimuno GOS, Clasado Biosciences) orally 2.8 grams daily for 6 weeks does not increase clinical remission or improve IBD severity scores when compared with baseline. However, subgroup analyses suggest that taking GOS may reduce the frequency and urgency of loose stools. The validity of this study is limited by the lack of a comparator group (107728).
• Urticaria. It is unclear if oral GOS are beneficial for the prevention of urticaria in infants. Details: A small clinical study in newborns at risk for atopic disease shows that feeding a formula containing a combination of GOS and fructo-oligosaccharides 8 grams/L as often as necessary for 6 months reduces the risk of developing urticaria at 2 years of age when compared with placebo. Approximately 1.5% of infants in the GOS group developed urticaria, compared to 10.3% of those in the placebo group (99223). More evidence is needed to rate GOS for these uses.

(Read more about GALACTO-OLIGOSACCHARIDES (GOS))

INSUFFICIENT RELIABLE EVIDENCE to RATE

• 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.

(Read more about LIPASE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• 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.

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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).

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LIKELY SAFE ...when consumed in amounts commonly found in foods. GOS are found in various foods, including dairy products, legumes, and some root vegetables (26702,26732).

POSSIBLY SAFE ...when used orally and appropriately, short-term. GOS or foods fortified with GOS up to 20 grams daily have been safely used in clinical research for up to 30 days (21191,26706,26712,26727,99224,106526,106529,107715,107729). The European Food Safety Authority has concluded that consuming food products providing GOS up to 16.2 grams daily does not present safety concerns (106530). This agency has not evaluated the safety of higher doses in food products.

CHILDREN: POSSIBLY SAFE
when used orally in breast milk or infant formulas containing up to 7. 2 grams/L of GOS provided as the sole prebiotic or in combination with other prebiotics, including fructo-oligosaccharides or polydextrose, daily for 4-12 months (26708,26709,26710,26720,99211,99212,99215,99218,99222,99223,106527). ...when used in doses of up to 10 grams daily for 3 weeks in females 10-13 years of age (99210).

PREGNANCY AND LACTATION: LIKELY SAFE
when consumed in amounts commonly found in foods.

PREGNANCY AND LACTATION: POSSIBLY SAFE
when used orally. GOS have been safely used in clinical research in doses of about 4.5 grams daily from week 25 of pregnancy until delivery (26721).

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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.

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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.

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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).

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IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, GOS might reduce the effects of immunosuppressants.  Details Human and animal studies suggest that GOS may stimulate the immune system (26711,26723). This could theoretically alter the effects of immunosuppressant medications.

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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).

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General ...Orally, GOS seem to be well tolerated in infants, children, and adults.
Most Common Adverse Effects:
Orally: Bloating, constipation, diarrhea, flatulence, and increased stool frequency.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis in sensitive individuals.

Dermatologic ...Orally, giving a formula supplemented with 4 grams/L of GOS and polydextrose (1:1 ratio) to infants has been associated with an increased incidence of atopic dermatitis in one clinical study (26709). However, most other clinical research in infants at risk of atopy shows that GOS-containing formula may actually reduce the risk of developing atopic dermatitis (26707,26708,99223).

Gastrointestinal ...Orally, galacto-oligosaccharides may cause bloating, flatulence, and increased stool frequency (26706,26709,26724,99217,99222). Giving a formula supplemented with 4 grams/L of GOS and polydextrose (1:1 ratio) to infants has been associated with an increased incidence of gastrointestinal adverse effects, primarily constipation and diarrhea, in one clinical study (106527). However, it is unclear if this was due to GOS, polydextrose, or the combination.

Immunologic ...Orally, GOS have been rarely associated with allergic reactions, including anaphylaxis. Research in these patients shows that people who are previously sensitized to Blomia tropicalis, a common dust mite in Southeast Asia, may also experience allergic reactions after consumption of GOS. Blomia tropicalis contains glycosylated allergens that have IgE mediated cross-reactivity to GOS (102508).

Psychiatric ...Orally, giving infants a formula supplemented with 8 grams/L of a 50:33:17 mixture of polydextrose, GOS, and lactulose has been associated with increased infant irritability when compared with control formula (26709). However, it is not known if this was related to the GOS, other ingredients, or the combination. An increase in irritability did not occur in infants given a formula supplemented with 4 grams/L of polydextrose and GOS (1:1 ratio) (26709,106527).

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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).

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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).

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