Acti-Zyme [Discontinued] by Nature's Plus

POSSIBLY EFFECTIVE

• Irritable bowel syndrome (IBS). A specific strain of oral brewer's yeast seems to be beneficial for some IBS symptoms. Details: A meta-analysis of results from two clinical studies shows that taking the specific brewer's yeast strain CNCM I-3856 500 mg or 1000 mg daily, standardized to 8 billion colony-forming units (CFUs) per gram, for up to 12 weeks might reduce abdominal pain and discomfort and improve stool consistency in patients with constipation-predominant IBS. It seems to take at least one month for any benefits to occur (95611). Another small clinical study shows that taking the same product as 2 billion CFUs twice daily in addition to standard treatment for 8 weeks modestly improves abdominal pain and stool consistency when compared with standard treatment alone. Benefits were evident within 4 weeks and were found in patients with diarrhea-predominant, constipation-predominant, and mixed-type IBS (105170). Additionally, a large clinical trial in patients with constipation-predominant IBS shows that taking the same brewer's yeast product 8 billion CFUs daily for 8 weeks increases the likelihood of abdominal pain response, defined as a 30% or greater reduction in average daily abdominal pain scores, by 33% and improves quality of life scores when compared with placebo. However, no improvements in bloating, flatulence, stool frequency, or stool consistency were reported (111108).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there has been interest in using oral or topical brewer's yeast for acne, there is insufficient reliable information about the clinical effects of brewer's yeast for this condition.
• Allergic rhinitis (hay fever). It is unclear if oral dried, inactive brewer's yeast is beneficial for allergic rhinitis. Details: Preliminary clinical research in adults with seasonal allergies shows that taking a specific dried, inactive brewer's yeast preparation (EpiCor, Embria Health Sciences) 500 mg once daily for 12 weeks reduces the median severity of nasal congestion by 14%, the median severity of rhinorrhea by 19%, and the median number of days with nasal congestion by 12.5 days during weeks of highest pollen counts when compared with placebo. However, taking this brewer's yeast preparation does not appear to reduce ocular symptoms or sneezing. Also, it does not appear to improve nasal or ocular symptoms during weeks in which pollen counts are lower (92821).
• Clostridioides difficile infection. Although there has been interest in using oral brewer's yeast for C. difficile infection, there is insufficient reliable information about the clinical effects of brewer's yeast for this condition.
• Diarrhea. Although there has been interest in using oral brewer's yeast for diarrhea, there is insufficient reliable information about the clinical effects of brewer's yeast for this condition.
• Furuncles (boils). Although there has been interest in using oral brewer's yeast for furuncles, there is insufficient reliable information about the clinical effects of brewer's yeast for this condition.
• Hypercholesterolemia. It is unclear if oral brewer's yeast is beneficial for hypercholesterolemia. Details: Preliminary clinical research shows that taking brewer's yeast 20 grams, containing chromium 48 mcg, daily for 8 weeks decreases levels of total cholesterol by 24-26 mg/dL and increases levels of high-density lipoprotein (HDL) cholesterol by 5-6 mg/dL when compared to baseline in normocholesterolemic and hypercholesterolemic patients (37178).
• Influenza. It is unclear if oral dried, inactive brewer's yeast is beneficial for influenza. Details: Preliminary clinical research shows that taking a specific dried, inactive brewer's yeast preparation (EpiCor, Embria Health Sciences) 500 mg daily for 12 weeks reduces the incidence of common cold or flu-like symptoms by 10% to 20% when compared with placebo in adults with no history of influenza vaccination. Taking this preparation does not appear to reduce the duration or severity of cold or flu-like symptoms that do occur in these patients (92822). However, in patients recently vaccinated for influenza, clinical research shows that taking this same preparation 500 mg daily for 12 weeks reduces the risk of developing symptoms of the common cold or flu by about 11% and reduces the duration of symptoms that develop by 0.85 days when compared with placebo (16117).
• Premenstrual syndrome (PMS). Oral brewer's yeast 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 combination product (Sillix Donna, Giuliani) containing folic acid, vitamin B6, vitamin E, various minerals, and brewer's yeast might help reduce scores on the Menstrual Distress Questionnaire (MDS) when compared to baseline (7845). It is unclear if this benefit is due to brewer's yeast or the vitamins and minerals also contained in the preparation. More evidence is needed to rate brewer's yeast for these uses.

(Read more about BREWER'S YEAST)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral bromelain for allergic rhinitis, there is insufficient reliable information about the clinical effects of bromelain for this condition.
• Aromatase inhibitor-induced arthralgia. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with aromatase inhibitor-induced arthralgia shows that taking a specific combination product (Opera, Gam Farma), providing bromelain 20 mg, alpha-lipoic acid 240 mg, Boswellia serrata 40 mg, and methylsulfonylmethane 200 mg, daily for 6 months reduces arthralgia symptoms when compared to baseline (109570). The validity of these findings is limited by a lack of placebo control group. Further, it is unclear if these findings are due to bromelain, other ingredients, or the combination.
• Burns. Preliminary clinical research shows that topical bromelain is beneficial for burn debridement. It is unclear if topical bromelain is beneficial for scar prevention. Details: Preliminary clinical research and chart reviews show that gels formulated with proteolytic enzymes derived from bromelain (Debridase or NexoBrid, MediWound Ltd.), applied under an occlusive dressing for 4 hours, help debride burns, including chemical and electrical burns, in children and adults (18275,91113,103297,108149). However, only one of these studies compared the bromelain-based enzymatic debridement product to standard of care. In this study, which included surgical excision or non-surgical debridement, bromelain-derived gel decreased the time to complete debridement by 6.5 days, reduced the risk of surgical excision by 65%, and reduced the risk for autografts by 48%. However, in the long-term, there appeared to be no difference in quality of life or scarring between groups (91113).
• Cancer. Although there has been interest in using oral bromelain for cancer, there is insufficient reliable information about the clinical effects of bromelain for this condition.
• Chemotherapy-induced peripheral neuropathy. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with chemotherapy-induced peripheral neuropathy shows that taking a specific product (Opera, Gamfarma s.r.l.) containing bromelain 20 mg, alpha-lipoic acid 240 mg, methylsulfonylmethane (MSM) 200 mg, and boswellia 40 mg daily for 12 weeks reduces overall pain when compared with baseline (96449). The validity of these findings is limited by the lack of a control group. Additionally, it is not clear if benefit is due to alpha-lipoic acid, the other ingredients, or the combination.
• Diabetes. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small observational study in patients with a family history of type 1 diabetes found that taking a specific product (Mucos Pharma) containing bromelain 90 mg. rutin 100 mg, and trypsin 48 mg daily for 24 months is not associated with reduced incidence of type 1 diabetes at 8 years (99472).
• Diabetic foot ulcers. Although there has been interest in using topical bromelain for diabetic foot ulcers, there is insufficient reliable information about the clinical effects of bromelain for this condition.
• Exercise-induced muscle soreness. It is unclear if oral bromelain is beneficial for preventing exercise-induced muscle soreness. Details: One small clinical study shows that taking bromelain 300 mg three times daily, immediately following an intense exercise regimen, does not reduce delayed onset muscle soreness and has no effect on pain, flexibility, or skeletal weakness when compared with either ibuprofen 400 mg three times daily or placebo (10622). However, a small clinical study shows that taking a combination protease tablet containing bromelain 50 mg, trypsin 75 mg, papain 50 mg, amylase 10 mg, lipase 10 mg, lysosome 10 mg, and chymotrypsin 2 mg, four times in one day before downhill running, can improve recovery of contractile muscle function and decrease muscle soreness when compared with placebo (67838). It is unclear if these effects are due to bromelain, other ingredients, or the combination.
• Exercise-induced respiratory infections. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in non-elite male runners shows that taking a combination product (Wobenzym Plus, Mucos Pharma) providing bromelain 540-1080 mg, rutin 600-1200 mg, and trypsin 288-576 mg daily for 3 weeks, starting one week before a marathon, does not reduce the risk of a post-race respiratory tract infection when compared with placebo (96766).
• Kidney stones (nephrolithiasis). It is unclear if oral bromelain is beneficial for kidney stone expulsion. Details: Observational research in patients with 4-10 mm kidney stones found that adding bromelain to tamsulosin is associated with a 12% increased rate of spontaneous stone expulsion when compared to tamsulosin alone (100752).
• Knee pain. It is unclear if oral bromelain is beneficial for knee pain. Details: Preliminary clinical research shows that taking bromelain (Bromelin, Lichtwer Pharma Ltd.) orally for 30 days can reduce mild, acute (duration of less than 3 months) knee pain in otherwise healthy patients when compared to baseline. A daily dose of 400 mg seems to be more effective than 200 mg daily for relieving pain, stiffness, and physical function of the knee, with reductions in symptom scores of 59% and 41%, respectively (11457).
• Lymphedema. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some clinical research in patients who have undergone a mastectomy shows that taking a specific combination product containing bromelain, rutin, pancreatin, papain, trypsin, and chymotrypsin (Wobenzym N, Mucos Pharma) daily for 7 weeks reduces arm swelling associated with lymphedema when compared with diuretics (24560). Other preliminary clinical research in patients with primary or secondary lymphedema of the upper or lower limbs shows that taking a different combination product containing bromelain 100 mg, rutin 300 mg, and sweet clover 100 mg daily for 6 months decreases pitting, limb volume, pain, and quality of life when compared to baseline (103298). The validity of these results is limited by the lack of a control group. Additionally, it is unclear if these findings are due to bromelain, other ingredients, or the combination.
• Multiple sclerosis (MS). Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A preliminary clinical study in patients with relapsing-remitting MS shows that taking an enzyme combination containing bromelain 90 mg, rutin 100 mg, and trypsin 48 mg per tablet for at least 3 months does not affect the progression of disability, relapse rate, or central nervous system lesions when compared with placebo (99468). The validity of these results is limited by the short duration of treatment.
• Ocular floaters. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in patients with spontaneous symptomatic vitreous opacities (ocular floaters) shows that taking oral mixed fruit enzyme capsules containing bromelain 190 mg, papain, and ficin once, twice, or three times daily for 3 months eliminates floaters in 55%, 63%, and 70% of patients, respectively, when compared with an elimination rate of 5% with vitamin C as a control. Additionally, patients with vitreous hemorrhage-induced symptomatic vitreous opacities taking the mixed fruit enzyme capsules 3 times daily for 3 months reduced intraocular blood by 56% and improved visual acuity, but these effects were not found for lower doses and shorter durations when compared with a control (111650). It is unclear if these effects are due to bromelain, other ingredients, or the combination.
• Osteoarthritis. It is unclear if oral bromelain is beneficial for osteoarthritis. Details: A small clinical trial shows that taking bromelain 800 mg daily for 12 weeks as an adjunctive treatment for moderate to severe knee osteoarthritis is no more effective than placebo for improving symptom scores (18274). Other preliminary clinical research shows that taking bromelain 500 mg daily for 4 weeks for mild to moderate knee osteoarthritis is less effective than diclofenac 100 mg daily for improving quality of life, joint pain, and joint function (96216). However, preliminary clinical research shows that oral combination products containing bromelain can reduce pain and improve function in knee osteoarthritis (6252,91104,91106,92235,99467,99477,103299). Bromelain 180 mg has been used in combination with trypsin 144 mg and rutin 200 mg (Phlogenzym, Mucos Pharma GMBH; Wobenzym, Mucos Pharma GmbH) three times daily for 3-12 weeks, with effects comparable to diclofenac, usually taken as 50 mg three times daily for one week, then twice daily thereafter. This product also reduces the need for rescue analgesics by 95% when compared with placebo (6252,91104,92235,99467,99477). Other studies have used a specific combination supplement (AINAT, Laboratoire de Rhumatologie Appliquée) containing Devil's claw 600 mg, turmeric 400 mg, and bromelain 300 mg, taken 2-3 times daily for 2-8 weeks (91106) or a combination of bromelain 250 mg and papain 250 mg (Nature's Life Bromelain & Papain, NutraMarks, Inc.) twice daily, plus aceclofenac 100 mg twice daily for 6 weeks (103299).
• Pain (acute). It is unclear if oral bromelain is beneficial for acute pain. Details: A meta-analysis of 9 small clinical studies in patients experiencing acute pain due to various etiologies shows that taking bromelain slightly improves subjective pain scores and allows patients to open their mouth wider after oral operations when compared with a control (113513).
• Parturition. Although there has been interest in using oral bromelain for shortening the duration of labor, there is insufficient reliable information about the clinical effects of bromelain for this purpose.
• Periodontitis. It is unclear if oral bromelain is beneficial for periodontitis. Details: A very small clinical study in adults with periodontitis shows that taking bromelain 500 mg (Anaheal) twice daily for one week after undergoing pocket elimination surgery reduces bleeding on probing but does not improve gingival index, plaque index, or probing pocket depth when compared with placebo when assessed five weeks after surgery (111691). The validity of these effects is limited by a very small sample size and inadequate statistical power.
• Pityriasis lichenoides chronica (PLC). It is unclear if oral bromelain is beneficial for PLC. Details: A case series suggests that taking bromelain 40 mg orally three times daily for one month, then twice daily for a second month, then once daily for a third month, helps treat episodes of PLC when compared to baseline (18280).
• Postoperative pain. While evidence is mixed, some small clinical studies suggest that oral bromelain reduces postoperative pain after wisdom tooth extraction. It is unclear if bromelain improves pain after other surgical procedures. Details: Meta-analyses and clinical research in a small number of patients undergoing wisdom tooth extraction shows that bromelain modestly reduces pain for up to 8 days when compared with control (91109,91110,100750,100751). Also, three small clinical trials show that bromelain 160-1500 mg, taken in 3-4 divided doses daily for 4-6 days, reduces dental pain and swelling similarly to taking ketoprofen 100 mg twice daily, diclofenac sodium 25 mg four times daily, or aceclofenac 100 mg twice daily (91109,91110,110546). In contrast, several other small clinical studies show that taking bromelain does not reduce swelling or pain after wisdom tooth extraction when compared with placebo (91107,96214,96215). These studies might have not been sufficiently powered to detect a smaller effect. Meta-analyses also suggest that bromelain does not appear to have a significant effect on postoperative swelling or trismus (100750,100751). However, a more recent study in patients undergoing wisdom tooth extraction shows that taking bromelain 500 mg three times daily for 5 days reduces the severity of postoperative swelling and trismus when compared with aceclofenac, a nonsteroidal anti-inflammatory drug (NSAID) used in some European and Asian countries (110546). Bromelain, in combination with other ingredients, has also been evaluated for reducing pain after rotator cuff tear repair. Clinical research shows that taking a specific supplement (Tenosan, Agave) containing bromelain 50 mg, arginine-L-alpha-ketoglutarate 500 mg, methylsulfonylmethane (MSM) 550 mg, hydrolyzed collagen type I 300 mg, vitamin C 60 mg, and Vinitrox 125 mg daily for 3 months decreases shoulder pain, but does not improve shoulder function, in postoperative patients (19322).
• Postoperative swelling. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small preliminary clinical study in patients undergoing surgery of the jaw shows that taking an enzyme combination of bromelain 180 mg, rutin 200 mg, and trypsin 96 mg twice daily for 5 days in addition to standard treatment reduces soft-tissue thickness (indicating the amount of swelling) at most of the nine assessed facial points when compared to control (99476).
• Rhinosinusitis. It is unclear if oral bromelain is beneficial for rhinosinusitis. Details: Several small clinical trials show that short-term and long-term use of bromelain reduces symptoms of acute and chronic sinusitis, especially nasal mucosal inflammation and edema (18276,18277,18278,18279,91105). The trials used bromelain 40 mg orally (usually the product Ananase) four times daily for six days as an adjunct to antibiotics (18276,18278,18279) or 6 bromelain tablets each containing enzymes of 500 International Pharmaceutical Federation (FIP) units for 12 weeks (91105). Bromelain is usually taken in combination with decongestants, antihistamines, and/or antibiotics. However, the studies have a number of methodological problems, and results are inconsistent. Bromelain has also been evaluated as part of a combination product. A small study in patients over 12 years old with chronic sinusitis shows that taking a combination product containing bromelain 200 mg, Boswellia serrata, black currant, and vitamin D (Flogostop Forte, Humana Italia S.p.A) 1-2 times daily for 15-30 days as an adjunctive therapy to inhaled corticosteroids modulates hyperemia of the mucosa, rhinorrhea, and local inflammation when compared with inhaled corticosteroids alone and baseline (111501). It is unclear if these findings are due to bromelain, other ingredients, or the combination.
• Sprains. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A preliminary clinical study in patients with a sprained ankle shows that taking a specific enzyme combination (Phlogenzym, Mucos Pharma) containing bromelain 90 mg, trypsin 48 mg, and rutin 100 mg, or taking different combinations of the individual enzymes three times daily for 10 days, is no more effective for relieving pain than placebo (99473).
• Tendinopathy. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with Achilles tendon insertional tendinopathy shows that taking two sachets of a specific supplement (Tenosan, Agave, Prato, Italy) containing a total of bromelain 100 mg, arginine-L-alpha-ketoglutarate 1000 mg, methylsulfonylmethane (MSM) 1100 mg, hydrolyzed collagen type I 600 mg, vitamin C 120 mg, and Vinitrox 25 mg orally for 60 days improves function and pain when compared with placebo (19321).
• Urinary tract infections (UTIs). Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial shows that a combination of bromelain 50 mg and trypsin 1 mg (Kimotab, Mochida Pharmaceutical), taken in a dose of 8 tablets daily for 2 days, does not improve subjective symptoms of UTIs when compared with placebo (18282).
• Venous leg ulcers. Although there has been interest in using topical bromelain for venous leg ulcers, there is insufficient reliable information about the clinical effects of bromelain for this condition.
• Wound healing. It is unclear if enzymatic debridement with bromelain improves the healing of various types of chronic wounds. Details: A meta-analysis of 12 small clinical studies shows that topical bromelain reduces time to complete debridement by around 6 days but has no effect on time to healing when compared with a control (113513). However, the validity of these effects is limited by significant publication bias and a small number of studies per outcome. One small clinical study, included in the analysis above, of patients with chronic wounds related to diabetes, surgery, trauma, or venous insufficiency shows that use of bromelain-based enzymatic debridement (EscharEx, MediWound Ltd), administered as up to ten daily applications of 4 hours each, increases the incidence of complete debridement over the next 6 months to 55% of patients, compared with only 29% of those using the bromelain-free gel. However, there was no difference in changes in wound area, non-viable tissue area, or the incidence or time to complete wound closure (108148). More evidence is needed to rate bromelain for these uses.

(Read more about BROMELAIN)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Constipation. Small clinical studies suggest that oral FOS may modestly improve symptoms in patients with constipation when used in combination with probiotics. The benefits of FOS when used alone are unclear. Details: Most clinical research has evaluated the use of FOS for constipation in conjunction with probiotics. Preliminary clinical research in adults with chronic functional constipation shows that taking an unspecified dose of a specific product (Hexbio) consisting of FOS, Lactobacillus acidophilus, Lacticaseibacillus casei, Lactococcus lactis, Bifidobacterium bifidum, Bifidobacterium longum, and Bifidobacterium infantis orally twice daily for 7 days increases defecation frequency by 3-fold when compared with placebo. Taking this product also improved patient reported symptoms of straining, lumpy hard stools, and incomplete evacuation sensations (90266). Other clinical research in adult females with constipation shows that taking a different product (Lactofos, SKL Functional Nutrition Ltda.) containing FOS 6 grams and Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactobacillus acidophilus, and Bifidobacterium lactis 0.1-1 billion colony-forming units each, orally twice daily for 30 days, modestly increases the frequency of evacuation and decreases constipation severity when compared with placebo (90300). It is unclear if these effects are due to FOS, other ingredients, or the combination. In children aged 4-8 years with functional constipation, preliminary clinical research shows that taking a mixture of FOS 0.45 grams and polydextrose 4.17 grams orally daily for 45 days improves the weekly frequency of bowel movements, clinical manifestations of constipation, and quality of stool type when compared with baseline (106482). It is unclear if these effects are due to FOS, polydextrose, or the combination. Additionally, the validity of these findings is limited by the lack of a comparator group. Clinical research evaluating the use of FOS alone is limited. Preliminary clinical research in elderly males shows that taking FOS alone 3-10 grams daily for 30 days increases the frequency of defecation by 1.5-fold when compared with baseline (8505). The validity of this study is limited by the lack of a comparator group. In non-breastfeeding infants 6-24 months of age with constipation, preliminary clinical research shows that fortifying formula or milk with FOS daily for 4 weeks increases the frequency of soft stools by 33% and decreases the frequency of straining by 55% when compared with placebo. However, the use of FOS did not increase the percentage of infants who achieved normal bowel pattern. The daily dose of FOS was 6 grams for infants 6-8.9 kg, 9 grams for infants 9-11.9 kg, and 12 grams for infants over 12 kg (98651).
• Diabetes. Oral FOS has only been evaluated in combination with probiotics; its effect when used alone is unclear. Details: Preliminary clinical research in adults with type 2 diabetes shows that taking a combination product containing FOS 500 mg, Bacillus coagulans 100 billion spores, Lacticaseibacillus rhamnosus 10 billion colony-forming units (CFUs), and Lactobacillus acidophilus 1 billion CFUs once daily for 12 weeks reduces fasting blood glucose by 17 mg/dL, compared with an increase of 3 mg/dL with placebo. However, taking this product did not affect body weight, waist circumference, or cholesterol levels. It is unclear if this effect is due to FOS, other ingredients, or the combination (107731).
• Hematopoietic stem cell transplant (HSCT). It is unclear if oral FOS is beneficial in patients undergoing HSCT. Details: Preliminary clinical research in patients undergoing an allogeneic HSCT shows that taking a specific oral FOS supplement, (Fibrulose F97, Cosucra Groupe) 5-15 grams daily for 21 days, beginning 5 days before transplant, does not reduce acute graft-versus-host disease, blood stream infections, or Clostridioides difficile infections or improve overall survival when compared with control (107931). However, this study may have been inadequately powered to detect a difference between groups.
• Hypercholesterolemia. Although there has been interest in using oral FOS for hypercholesterolemia, there is insufficient reliable information about the clinical effects of FOS for this purpose.
• Obesity. Although there has been interest in using oral FOS for obesity, there is insufficient reliable information about the clinical effects of FOS for this purpose.
• Osteoporosis. Oral FOS has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in postmenopausal adults shows that taking a specific FOS product (NutraFlora, Ingredion Inc.) 3.2 grams plus calcium 800 mg daily for 24 months reduces the decline in total-body bone mineral density (BMD) when compared with calcium alone, but not when compared with a maltodextrin control. In a subgroup of patients with osteopenia, this combination reduced the decline in BMD in the lumbar vertebrae when compared with calcium alone or a maltodextrin control (94931).
• Travelers' diarrhea. It is unclear if oral FOS is beneficial for preventing traveler's' diarrhea. Details: Preliminary clinical research shows that taking FOS 10 grams orally daily for 4 weeks, starting 2 weeks before traveling to a medium- to high-risk destination, does not reduce the incidence of travelers' diarrhea when compared with placebo (10373). However, the study may have been inadequately powered to detect a difference between groups. More evidence is needed to rate FOS for these uses.

(Read more about FRUCTO-OLIGOSACCHARIDES (FOS))

EFFECTIVE

• Lactose intolerance. Lactase is effective for reducing gastrointestinal symptoms from consuming lactose in lactose intolerant individuals. Details: Multiple clinical trials show that taking lactase orally is effective for reducing GI symptoms in lactose-intolerant people when used before the consumption of lactose or when added to milk prior to consumption (2371,2372,2373,106669).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Colic. It is unclear if oral lactase is beneficial in infants with colic. Details: Preliminary clinical research in infants with colic shows that supplementing human milk or formula with lactase (Crosscare Ltd) for 10 days reduces breath hydrogen levels, but not time spent crying, when compared with placebo. However, approximately 30% of infants in this study were considered to be noncompliant. When only infants considered to be compliant were included in the analysis, time spent crying during the 10-day treatment period was reduced by about 6 hours in the lactase group when compared with placebo (96347). In two other small trials, giving 5 drops of a specific lactase formulation (Colibid, RG Pharmaceutica or Yamoo, Walter Bushnell) to infants aged 0-6 months with colic before each feed, or 4 times a day, for 2-4 weeks significantly reduces crying time and fussing time when compared with placebo (104107,112190). However, measures of crying time were based on subjective parent recall only.
• Prematurity. It is unclear if oral lactase is beneficial in premature patients. Details: Clinical research shows that giving fortified human milk or preterm formula treated with lactase drops (Lactaid, McNeil Consumer Products Company) to preterm infants does not improve weight gain, feeding tolerance, weekly length gain, or gain in head circumference by 36 weeks' gestational age or discharge from the hospital (whichever comes first) when compared with giving untreated milk or formula (96346). More evidence is needed to rate lactase for these uses.

(Read more about LACTASE)

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)

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

(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

POSSIBLY SAFE ...when used orally and appropriately, short-term (7845,16117). A specific dried, inactive brewer's yeast preparation (EpiCor, Embria Health Sciences) has been used with apparent safety at a dose of 500 mg once daily for 12 weeks (92821,92822). A specific living brewer's yeast strain CNCM I-3856 has been used with apparent safety at a dose of 500-1000 mg daily (standardized to 8 billion colony-forming units per gram) for up to 12 weeks (95611,105170,111108). There is insufficient reliable information available about the safety of the long-term use of brewer's yeast or about the safety of using brewer's yeast topically.

CHILDREN:
There is insufficient reliable information available about the safety of brewer's yeast as a probiotic or postbiotic in children of any age. Cases of bacteremia have occurred rarely in preterm infants given other probiotics (102416,111610,111612,111613,111850,111852,111853). The US Food and Drug Administration (FDA) has issued a warning about cases of serious infections caused by probiotics reported in very preterm or very low birth weight infants under 1000 grams (111610). Similarly, the American Academy of Pediatrics does not support the routine administration of probiotics to these infants due to conflicting data on safety and efficacy (111608).

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

(Read more about BREWER'S YEAST)

POSSIBLY SAFE ...when used orally and appropriately. Doses up to 240 mg daily have been used safely for up to a year (6252,6253,10622,11457,18281,18284,91104,91105,91106,91111)(96449,103298). Higher doses up to 3200 mg daily have been used safely, short-term (18283,110546). ...when used topically and appropriately. Bromelain has been used safely as a debriding agent for up to 4 hours (18275,91113,103297,108148,108149).

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

(Read more about BROMELAIN)

POSSIBLY SAFE ...when used orally and appropriately, alone or in combination with probiotics, in doses up to 30 grams daily for up to 4 weeks (741,745,8505,90266,107729,107931). ...when a specific FOS product (NutraFlora, Ingredion Inc.) is used orally in combination with calcium at doses up to 3.2 grams daily for up to 24 months (94931).

CHILDREN: POSSIBLY SAFE
when short-chain FOS are included in approved infant formulas for healthy term infants at a level of up to 4 grams/L or 1 gram/kg daily (94929,94930,98651).

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

(Read more about FRUCTO-OLIGOSACCHARIDES (FOS))

LIKELY SAFE ...when used orally and appropriately with lactose-containing foods. Lactase has Generally Recognized as Safe (GRAS) status in the US when prepared from Candida pseudotropicalis or Kluyveromyces lactis (104108,104109). Lactase has been used safely in doses up to 9900 international units (IU) and up to 13,500 food chemical codex (FCC) units (2371,2372,2373,106669).

CHILDREN: LIKELY SAFE
when used orally and appropriately with lactose-containing foods.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately with lactose-containing foods.

(Read more about LACTASE)

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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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.

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking brewer's yeast with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research shows that taking chromium-containing brewer's yeast can decrease levels of blood glucose in diabetic patients being treated with antidiabetes drugs (37157).

ANTIFUNGALS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking antifungals with some brewer's yeast products might decrease the effectiveness of brewer's yeast.  Details Some brewer's yeast products contain live yeast. Therefore, simultaneously taking antifungals might kill a significant number of the organisms (4363).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking brewer's yeast with lithium might cause additive effects and side effects.  Details Some brewer's yeast products contains lithium (37179).

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = D Theoretically, taking brewer's yeast with MAOIs might increase the risk of hypertension.  Details Brewer's yeast contains tyramine. Taking brewer's yeast with MAOIs might increase the risk for hypertensive crisis (2).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Bromelain may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details There is one case report of a patient experiencing minor bruising while taking bromelain with naproxen (14806). Bromelain is thought to have antiplatelet activity (10639,14806,18285,18286,37234). Whether this interaction is of concern with topical bromelain is unclear. Interference with coagulation of burn wounds has been reported in a patient receiving bromelain-based enzymatic debridement. However, observational research has found that topical bromelain debridement is not associated with increases or decreases in laboratory markers of coagulation when compared with surgical debridement (110547).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, bromelain might increase levels of tetracycline antibiotics.  Details Laboratory research suggests that bromelain might increase the absorption of tetracycline antibiotics. However, a study in healthy adults reported no difference in tetracycline plasma levels when a 500 mg dose was taken with or without bromelain 80 mg (14296).

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General ...Orally, brewer's yeast seems to be well tolerated in most patients when used short-term.
Most Common Adverse Effects:
Orally: Flatulence, migraine.
Serious Adverse Effects (Rare):
Orally: There is concern that brewer's yeast may cause fungemia in some people. It may also cause anaphylaxis in sensitive individuals.

Gastrointestinal ...Orally, brewer's yeast can cause intestinal discomfort and flatulence in hypersensitive individuals (2). Anal irritation and abdominal pain have been reported rarely (105170).

Immunologic ...Allergic reactions to brewer's yeast can occur in hypersensitive individuals. Symptoms include itching, urticaria, local or general exanthemas, and Quincke's edema (2). Rarely, anaphylaxis may occur. In one case, a 33-year-old male experienced dyspnea, chest tightness, and throat tightness shortly after ingesting a few sips of craft beer brewed using brewer's yeast. The patient took diphenhydramine, and symptoms improved prior to his arrival in the emergency department. While the patient had no history of hypersensitivity to other beers from the same brewery, a positive skin test and oral challenge suggested that he was sensitive to the specific strain of brewer's yeast uniquely used only in the offending beer (111107).

Neurologic/CNS ...Orally, brewer's yeast can cause migraine-like headaches in sensitive individuals (2).

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General ...Orally, bromelain seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, flatulence, gastric upset, headache.
Topically: Pruritus, urticaria.

Dermatologic ...Topically, bromelain may cause dermal allergic reactions including urticaria, pruritus, and skin swelling (9184). Redness, swelling, burning, pain at the application site, and cellulitis have also been reported rarely (108148,113513). In one case, a fixed drug eruption with pruritis near the groin was reported in a 33-year-old male taking bromelain 50 mg orally daily for 10 days. After discontinuation of bromelain and treatment with topical corticosteroid, the lesion resolved. Upon re-challenge with bromelain, the lesion reappeared in the same area (103300).
In another case report, a 61-year-old male with a history of chronic lower leg ulceration secondary to chronic venous hypertension and recurrent deep vein thrombosis on rivaroxaban presented with a deep-dermal burn on his lower calf. Bromelain-based topical enzymatic debridement agent Nexobrid 2 grams was applied to the burn site. Thirty minutes later, the patient experienced two instances of hemorrhage at the site of debridement. The patient was stabilized and treated with fluids, packed red cells, and tranexamic acid, and then the Nexobrid was removed (111656). Caution should be used in patients with underlying coagulopathies.

Gastrointestinal ...Orally, bromelain may cause gastrointestinal disturbances, including diarrhea, nausea, vomiting, flatulence, and abdominal pain (9184,18274,18282,96216,113513).

Immunologic ...Immunoglobulin E (IgE)-mediated allergic reactions to bromelain may occur (9184).
If inhaled, bromelain may cause sensitization and allergic reactions such as asthma (37199,37215,37233). In case reports of occupational inhalation of bromelain, additional allergic symptoms included difficulty swallowing, throat itching, eye irritation, and rhinitis (37214).

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General ...Orally, FOS are generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, bloating, flatulence.

Gastrointestinal ...Orally, FOS may cause flatulence, belching, abdominal pain, intestinal sounds, constipation, and bloating. These symptoms can occur commonly in some patients, but are generally mild at doses under 10 grams per day (745,750,8509,98651,107931). However, a meta-analysis of 8 small clinical studies shows that taking FOS at doses ranging from 2.5 grams to 15 grams daily for up to 8 weeks does not increase the rate of abdominal pain, bloating, flatulence, or intestinal sounds when compared with control groups (110710).

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General ...Orally, lactase is generally well tolerated.

Immunologic ...A case of lactase-induced contact dermatitis and immunoglobulin E (IgE)-mediated allergic rhinoconjunctivitis has been reported in a worker exposed to powdered lactase. Allergy to lactase was confirmed by prick test, open application test, and chamber challenge test (96348).

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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, 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).

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