Digestive Enzymes by Top Secret Nutrition

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral black pepper for allergic rhinitis, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Asthma. Although there has been interest in using oral black pepper for asthma, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Athletic performance. Oral black pepper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in untrained males shows that taking a supplement containing black pepper extract 10 mg, caffeine 400 mg, capsicum extract 66.7 mg, and niacin 40 mg as a single dose prior to exercise does not improve strength, time to exhaustion, or maximal oxygen consumption when compared with placebo (37873).
• Depression. Although there has been interest in using oral black pepper for depression, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Diarrhea. Although there has been interest in using oral black pepper for diarrhea, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Dysmenorrhea. Although there has been interest in using oral black pepper for dysmenorrhea, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Dyspepsia. Although there has been interest in using oral black pepper for dyspepsia, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Fall prevention. It is unclear if inhaling black pepper oil as aromatherapy is beneficial for fall prevention in older adults. Details: One small clinical study in older adults shows that applying black pepper oil near the right side of the nose as an olfactory stimulant improves stability while the eyes are closed during a one-minute trial when compared with the application of water. The improvement with black pepper oil is comparable to the improvement seen with the application of lavender oil (29160). It is unclear if any benefit persists after inhalation of black pepper oil.
• Fatigue. It is unclear if oral black pepper is beneficial in patients with fatigue. Details: One small clinical trial in adults with below-average energy levels shows that taking black pepper 2 grams as a single dose does not improve sustained attention, motivation to perform cognitive tasks, or feelings of mental energy and mental fatigue when compared with placebo (91731).
• Flatulence. Although there has been interest in using oral black pepper for flatulence, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Headache. Although there has been interest in using oral black pepper for headache, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Insect bite. Topical black pepper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial shows that applying a specific product (Trikatu) containing black pepper, long pepper, and ginger, as well as camphor, eucalyptus oil, and menthol, directly to mosquito bites does not reduce papule size, erythema, edema, or pruritis when compared with a control compound containing the same base ingredients but without the pepper and ginger components (89893).
• Obesity. Although there has been interest in using oral black pepper for obesity, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Pain (chronic). Although there has been interest in using topical black pepper for chronic pain related to various etiologies, including osteoarthritis, postherpetic neuralgia, and peripheral neuropathy, there is insufficient reliable information about the clinical effects of black pepper for these conditions.
• Rhinosinusitis. Although there has been interest in using oral black pepper for rhinosinusitis, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Sexual desire. Although there has been interest in using oral black pepper for increasing sexual desire, there is insufficient reliable information about the clinical effects of black pepper for this purpose.
• Smoking cessation. It is unclear if inhaling black pepper essential oil as aromatherapy is effective for smoking cessation. Details: One small clinical trial in adult male smokers who were deprived from smoking overnight shows that inhaling a vapor from the essential oil of black pepper, as needed over a 3-hour period, reduces cigarette cravings, negative feelings, and anxiety when compared with a placebo vapor (29159). Another small clinical study in patients addicted to dipping, chewing, or smoking tobacco shows that placing a drop of black pepper essential oil on tissue paper and inhaling for 2 minutes at least three times a day for 3 days reduces nicotine cravings when compared to baseline (90502).
• Swallowing dysfunction. It is unclear if inhaling black pepper oil as aromatherapy is beneficial in patients with swallowing dysfunction. Details: One small clinical study in post-stroke residents of nursing homes shows that one minute of olfactory stimulation with black pepper oil before each meal for 30 days decreases swallowing reflex latency by 11 seconds and increases the number of swallowing movements by 3.3 when compared to baseline (29161). A small clinical trial in children with neurological disorders who were on long-term enteral nutrition shows that applying black pepper oil to the nostrils or nasal cavity for one minute improves the amount of oral intake and swallowing movement in 63% of patients. Although oral intake increased, the need for enteral nutrition was not eliminated (29162).
• Vitiligo. It is unclear if topical piperine oil, a constituent of black pepper, is beneficial in patients with vitiligo. Details: A small clinical study in patients with vitiligo shows that applying piperine oil 1% daily in addition to receiving narrowband ultraviolet B (NB-UVB) light therapy every other day for 3 months improves repigmentation more rapidly when compared with using NB-UVB alone (103820). More evidence is needed to rate black pepper for these uses.

(Read more about BLACK PEPPER)

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)

POSSIBLY EFFECTIVE

• Antibiotic-associated diarrhea. Most research shows that oral Lactobacillus acidophilus, alone or in combination with other probiotics, seems to reduce the risk of antibiotic-associated diarrhea (AAD) in adults. Details: A meta-analysis of 18 clinical trials in hospitalized or outpatient adults shows that taking L. acidophilus alone or in combination with up to 8 other probiotic strains reduces the risk of AAD by 34% when compared with taking placebo (107635). One small clinical trial in elderly adults shows that AAD occurred in 17% of those taking L. acidophilus (Florajen Acidophilus) 20 billion colony-forming units (CFUs) three times daily, compared with 37% of those taking placebo (95400). A number of combination products have also demonstrated benefit for preventing AAD, including Bio-K+ Cl1285 which provides L. acidophilus CL1285, Lacticaseibacillus casei LBC80R, and Lacticaseibacillus rhamnosus CLR2 as 100 billion CFUs daily (25494,95402,95403); L. acidophilus and Bifidobacterium animalis subsp. lactis (90239); and Ecologic AAD which provides L. acidophilus NIZO 3678 and NIZO 3887, Lacticaseibacillus paracasei NIZO 3672, Lactiplantibacillus plantarum NIZO 3684, L. rhamnosus NIZO 3689, Ligilactobacillus salivarius NIZO 3675, Bifidobacterium bifidum NIZO 3804, Bifidobacterium animalis subsp. lactis NIZO 3680, and Enterococcus faecium NIZO 3886 (95405). However, some combination products have not demonstrated benefit. Clinical research shows that taking a combination of L. acidophilus and bifidobacteria or a combination of L. acidophilus and Lactobacillus delbrueckii subsp. bulgaricus (Lactinex) is not beneficial (90231,90239,92255,95385). An additional large clinical trial in children aged 3 months and up shows that taking L. acidophilus in combination with other probiotics does not reduce the risk of antibiotic-associated diarrhea when compared with taking placebo, when the more stringent definition is considered excluding diarrhea of other etiologies. However, the risk of diarrhea of any etiology is reduced by 35%. The probiotic supplement provided a total of 10 billion CFUs of L. acidophilus W37, Bifidobacterium bifidum W23, Bifidobacterium animalis subsp. lactis W51, Lactobacillus acidophilus W55, Lacticaseibacillus paracasei W20, Lactiplantibacillus plantarum W62, Lacticaseibacillus rhamnosus W71, and Ligilactobacillus salivarius W24 daily from the first day of antibiotic treatment until 7 days after treatment ended (110969).
• Bacterial vaginosis. Most clinical research shows that intravaginal application of Lactobacillus acidophilus may be helpful for the treatment of bacterial vaginosis. It is unclear if oral L. acidophilus is beneficial for the treatment or prevention of bacterial vaginosis. Details: One clinical trial shows that intravaginal suppositories containing 100 million to 1 billion colony-forming units (CFUs) of L. acidophilus (Vivag, Pharma Vinci A/S) given twice daily for 6 days improve bacterial vaginosis resolution rates when compared with placebo (13177). Another clinical trial shows that using 1-2 vaginal tablets containing viable L. acidophilus 10 million CFUs and estriol 0.03 mg per tablet (Gynoflor, Medinova) daily for 6 days increases cure rates when compared with placebo (13176). However, using this product in combination with metronidazole 400 mg twice daily for 7 days does not improve outcomes when compared with metronidazole alone (90237). Preliminary clinical research in patients with clinically defined bacterial vaginosis shows that daily intravaginal application with a douche providing L. acidophilus 1 billion CFUs per mL for 6 days might have beneficial effects on the vaginal flora. When compared with 52.5% of patients with bacterial vaginosis based on bacterial flora at baseline, 7.5% met this criteria 14 days after treatment had been completed (111788). Oral L. acidophilus has also been evaluated. Preliminary clinical research shows that eating yogurt 125 mL daily enriched with L. acidophilus for 2 months might slightly decrease the incidence of recurrent bacterial vaginosis (1245). L. acidophilus has also been investigated in an oral formulation in combination with other probiotics. Clinical research in patients with bacterial vaginosis cured within the past 48 hours shows that taking a product containing L. acidophilus in combination with other probiotics results in recurrence of vaginosis in 18.3% of patients, a statistically significant reduction compared with 32.1% of those using placebo. The mean time to recurrence was approximately 23 days longer in patients taking the lactobacilli. The product contained L. acidophilus 1.08 billion CFUs along with Lactobacillus crispatus LMG S-29995 and Levilactobacillus brevis (Lactogyn, Vésale Pharma, Belgium), and was taken twice daily for 7 days and then once daily for up to an additional 120 days (110950).
• Helicobacter pylori. Oral Lactobacillus acidophilus, usually in combination with other probiotics, seems to improve H. pylori eradication when used along with standard therapies. It is unclear if heat-killed L. acidophilus is beneficial for H. pylori eradication. Details: A meta-analysis of clinical studies utilizing probiotic products containing L. acidophilus shows that these products can improve H. pylori eradication rates 1.14- to 1.24-fold when taken in combination with triple therapy consisting of a proton-pump inhibitor (PPI), clarithromycin, and amoxicillin. Based on these results, about 7-11 patients would need to be treated in order for one additional patient to achieve complete remission (95394). Only one of the trials in this analysis investigated L. acidophilus alone; an additional 8 used L. acidophilus in combination with other probiotics. Individual clinical trials have shown that a combination of L. acidophilus, Enterococcus faecalis, and Bacillus subtilis 30 million colony-forming units (CFUs) total, taken in three divided doses daily, from 2 weeks prior tol 2 weeks after triple therapy increases H. pylori eradication when compared with triple therapy alone (90248). In children, a combination of L. acidophilus (strain 5) 94 million CFUs and Bifidobacterium bifidum (strain 12) 8.6 million CFUs in combination with a PPI, clarithromycin, and amoxicillin or metronidazole has been used daily for 2 weeks, followed by the probiotics alone for an additional 4 weeks (90602). However, other individual clinical trials have shown that L. acidophilus in combination with Lacticaseibacillus rhamnosus, Bifidobacterium bifidum, and Streptococcus faecium may not improve eradication rates when taken with triple therapy consisting of furazolidone, tetracycline, and lansoprazole (90279). Also, taking L. acidophilus along with six other probiotics in conjunction with bismuth quadruple therapy does not seem to improve H. pylori eradication rates when compared with placebo and bismuth quadruple therapy (90291). Also, taking L. acidophilus and L. casei without any standard H. pylori therapy does not improve H. pylori eradication rates in adults (12766). Heat-killed L. acidophilus has also been investigated in adults with H. pylori. Taking a lyophilized and inactivated culture of L. acidophilus (Lacteol Fort) containing 5 billion cells, 3 times daily for 10 days, modestly increases the eradication rate in patients using triple therapy of rabeprazole, clarithromycin, and amoxicillin for 7 days (8562).
• Irritable bowel syndrome (IBS). Some research shows that oral live Lactobacillus acidophilus, taken alone or in combination with other probiotics, may be beneficial for IBS. The effects of non-viable, heat-killed L. acidophilus are unclear. Details: Clinical research in adults with IBS shows that taking L. acidophilus DDS-1 10 billion colony-forming units (CFUs) daily for 6 weeks modestly reduces the severity of abdominal pain when compared with placebo. Also, 52% of patients experienced a more than 30% reduction in pain severity, compared with 16% of those taking placebo. There were also improvements in abdominal distention and duration of pain; however, there were no changes in bowel habits (107581). A meta-analysis shows that taking L. acidophilus improves the rate of symptom relief and reduces bloating severity when compared with placebo. However, other symptoms were not improved (110866). L. acidophilus has also been examined in combination with other probiotics. One clinical study shows that taking a specific combination product (Visbiome, ExeGi Pharma) containing L. acidophilus and 7 other species as 450 billion CFUs daily in two divided doses for 8 weeks improves abdominal bloating, but not abdominal pain, flatulence, or number of stools, in patients with diarrhea-predominant IBS (IBS-D) (11379). Another clinical study in patients with IBS-D shows that taking a specific multi-species probiotic (NordBiotic, MBM Biotix) containing L. acidophilus LA120, Lacticaseibacillus rhamnosus LR110, Lacticaseibacillus paracasei LPC100, Lacticaseibacillus casei LC130, Lactiplantibacillus plantarum LP140, Bifidobacterium breve BB010, Bifidobacterium longum BL020, Bifidobacterium bifidum BF030, Bifidobacterium animalis subsp. lactis BL040, and Streptococcus thermophilus ST250 as 2.5 billion CFUs total twice daily for 8 weeks improves overall symptom severity, as well as pain severity, pain frequency, and quality of life, when compared with placebo. Symptom severity was rated as mild by approximately 60% of those taking the probiotic mixture, compared with 30% of those taking placebo (107516). A small clinical trial shows that taking L. acidophilus NCFM plus Lactobacillus helveticus Lafti L10 (Lallemand Health Solutions) 5 billion CFUs each daily for 8 weeks modestly reduces flatus and overall symptoms, but not abdominal pain or bloating, when compared with taking placebo (111785). However, other probiotic compounds containing L. acidophilus have not demonstrated benefit in most patients with IBS. These include L. acidophilus NCFM 10 billion CFUs daily for 12 weeks; L. acidophilus, L. paracasei, and Bifidobacterium animalis subsp. lactis BB-12 (Cultura) 13-20 billion CFUs daily for 6 months; or L. acidophilus CL1285, L. casei LBC80R, and L. rhamnosus CLR2 50 billion CFUs each daily for 3 months (90236,94696,94697,95365,99789). Further research is needed to determine which IBS subtype, if any, is most likely to benefit. Heat-killed L. acidophilus has also been investigated in patients with IBS. One clinical study shows that taking capsules containing heat-killed L. acidophilus (Lacteol Fort) 20 billion colony-forming units (CFUs) daily for 6 weeks improves abdominal pain, bloating, and number and quality of stools when compared with placebo (7744). Also, in patients with IBS-D, observational research has found that use of heat-killed L. acidophilus (Lacteol LB) two capsules daily for one month modestly reduces pain and bloating and improves quality of life. The average weekly number of stools decreased by approximately 4.75. Also, the number of patients with watery stools was reduced from 54% at baseline to 19% (107535).

POSSIBLY INEFFECTIVE

• Atopic disease. Oral Lactobacillus acidophilus does not seem to be beneficial for preventing atopic disease in children. Details: A meta-analysis of clinical research shows that administering L. acidophilus during pregnancy, when breastfeeding, or to newborn infants might actually increase the risk of atopic sensitization (90251). However, the number of studies included in this analysis was limited.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A preliminary clinical study shows that taking a specific probiotic product containing L. acidophilus 5 billion colony-forming units (CFUs), Lactobacillus delbrueckii subsp. bulgaricus 5 billion CFUs, and Bifidobacterium bifidum 20 billion CFUs (Trenev Trio/Healthy Trinity, Natren) twice daily along with minocycline once every evening for 12 weeks improves inflamed and non-inflamed acne lesions in 82% of patients, compared to only 67% of patients treated with either the probiotic combination or minocycline alone (90270).
• Acute respiratory distress syndrome (ARDS). Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in premature infants shows that taking 6 billion CFUs of a combination of L. acidophilus NCDO 1748 and Bifidobacterium bifidum NCDO 2203 (UFC Inforan, Switzerland) from 7 days of age until 34 weeks postmenstrual age or discharge does not reduce the odds of ARDS when compared with a control group of infants not given these probiotics. The infants in this study were born at less than 32 weeks gestation and had a birthweight of less than 1500 grams (111794). This study is limited by the lack of randomization to treatment group; placement was based on year of birth.
• Allergic rhinitis (hay fever). It is unclear if oral Lactobacillus acidophilus is beneficial for allergic rhinitis prevention or treatment. Details: A small clinical trial in patients with perennial allergic rhinitis shows that taking heat-treated milk fermented with L. acidophilus L-92 100 mL daily for 8 weeks modestly reduces nasal symptoms and mucus, but not ocular symptoms, when compared with taking an acidified placebo milk. The milk provided approximately 30 billion L. acidophilus cells (25488). The effect of L. acidophilus as a probiotic is unclear from this study. Other clinical research shows that drinking 250 mL of fermented milk containing L. acidophilus La-5 5 billion colony-forming units (CFUs), Lacticaseibacillus rhamnosus GG 50 billion CFUs, and Bifidobacterium animalis subsp. lactis BB-12 50 billion CFUs from 36 weeks' gestation until 3 months postpartum does not reduce the incidence of allergic rhinitis in the child at 6 years of age when compared with placebo milk (96893).
• Asthma. It is unclear if oral Lactobacillus acidophilus can improve lung function in people with asthma. Details: A small clinical crossover study in patients with moderate asthma shows that consuming live active yogurt 225 grams, providing L. acidophilus 760 million colony-forming units (CFUs) per gram, twice daily for 1 month does not affect measures of lung function when compared with yogurt not containing L. acidophilus. All yogurt contained Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus (1244).
• Atopic dermatitis (eczema). Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of the available clinical research shows that intake of lactobacilli and bifidobacteria-based probiotics during gestation, followed by giving the probiotic to the newborn for the first 2-6 months of life, reduces the risk of developing atopic dermatitis by 40% over the next 6-24 months when compared with placebo, regardless of family history of atopy. However, only four of 10 studies included in the analysis used L. acidophilus as part of the probiotic combination; the results from these individual, small studies support the overall findings of the meta-analysis (107503). Some clinical research also shows that supplementation with 250 mL of fermented milk containing L. acidophilus La-5, Lacticaseibacillus rhamnosus GG, and Bifidobacterium animalis subsp. lactis BB-12 starting at 36 weeks' gestation and continuing until 3 months' postpartum, without supplementation in the infant, reduces the overall occurrence of atopic dermatitis in the child at 2 years of age. However, at 6 years of age, the effect appears to be inconclusive (96893). In children ages 1-3 years with moderate to severe atopic dermatitis, taking 5 billion colony-forming units (CFUs) of a combination of L. acidophilus DDS-1 and Bifidobacterium animalis subsp. lactis UABLA-12 along with fructo-oligosaccharides (FOS) (DDS Junior) twice daily for 8 weeks modestly reduces symptom severity and the need for topical corticosteroids when compared with placebo (110995).
• Bronchopulmonary dysplasia. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One large observational study in premature infants suggests that taking L. acidophilus 1 to 3 billion CFUs with Bifidobacterium longum subsp. infantis during the first month of life for the prevention of necrotizing enterocolitis was not associated with a reduced risk of bronchopulmonary dysplasia. The infants in this study were born between 22-29 weeks gestation and had a birthweight of less than 1500 grams (111771).
• Cancer. Although there has been interest in using oral Lactobacillus acidophilus for cancer prevention or treatment, there is insufficient reliable information about the clinical effects of L. acidophilus for this condition.
• Canker sores. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A systematic review and meta-analysis of mainly small and preliminary clinical trials shows that taking lactobacilli probiotics has a small effect on pain from canker sores. However, the dose and duration of probiotic and the specific species, as well as endpoints and results from individual studies, are mixed. One small study shows that taking a combination of L. acidophilus, Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, and Bifidobacterium animalis subsp. lactis reduces pain, but not the number of lesions or healing time, when compared with placebo. Another study shows that using lozenges providing inulin 0.13 gram along with L. acidophilus and B. animalis subsp. lactis 1.5 billion colony-forming units each reduces pain, but does not affect ulcer size or healing, when compared with Oracure gel (105146). Many of the individual studies may have been underpowered to detect a difference between groups.
• Cholestasis. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in premature infants shows that the risk of developing cholestasis is reduced from 22% to 6% in those given a blend of L. acidophilus, bifidobacteria, and Enterococcus faecalis (Peifeikang powder, Shanghai Xinyi Pharmaceutical Company) at least 5 million colony-forming units three times daily, from birth until implementation of total parenteral nutrition, when compared with infants not given this powder. In the infants that developed cholestasis, the severity was reduced, resulting in a reduction in the rate of cholestatic liver injury, feeding intolerance, and necrotizing enterocolitis. The number of days to reach full enteral feeding, days to normal weight gain, and days of hospitalization were reduced by approximately 2.8, 2.1, and 1.7 days, respectively (103448).
• Clostridioides difficile infection. It is unclear if oral Lactobacillus acidophilus is beneficial for preventing C. difficile occurrence or recurrence. Details: Current guidelines from the Infectious Diseases Society of America (IDSA) state that there is insufficient information to recommend administration of probiotics for the primary prevention of C. difficile-associated diarrhea (107538). Evidence from clinical and observational research investigating the effect of L. acidophilus on C. difficile occurrence or recurrence is weak. Most studies use this species in combination with one or more additional probiotic species, including as Bio-K+ CI1285, containing L. acidophilus CL1285 and L. casei LBC80R, and as Bio-K+ 50 Billion, containing L. acidophilus CL1285, Lacticaseibacillus casei LBC80R, and Lacticaseibacillus rhamnosus CLR2 (25494,90231,90934,95369,95403,107529). Observational research has found that providing the Bio-K+ 50 Billion product as 50-100 billion colony-forming units (CFUs) daily for 5 days to patients who are on antibiotics for at least 2 days reduces the hospital-wide incidence of C. difficile by approximately 40%. The incidence rate was decreased by at least 50% in the highest risk individuals taking this combination (107529).
• Colic. Oral inactivated Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study in infants with colic shows that giving a specific multi-ingredient product (Colimil Plus, Milte Italia SPA) containing inactivated L. acidophilus 1 billion colony-forming units, lemon balm 65 mg, and German chamomile 9 mg twice daily for 4 weeks reduces crying time similarly to Limosilactobacillus reuteri DSM 17938 100 million CFUs daily (96278). It is unclear how L. acidophilus compares with no treatment.
• Common cold. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in school children shows that taking a combination of L. acidophilus and Bifidobacterium bifidum (Infloran, Berna) 1 billion colony-forming units each twice daily for 3 months reduces the absolute percentage of school absence due to cold symptoms by 30% when compared with placebo (90286).
• Constipation. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that stool frequency is increased and symptoms of functional constipation in adults are improved with the use of a specific combination product (Hexbio) providing L. acidophilus, Lacticaseibacillus casei, Lactobacillus delbrueckii subsp. lactis, Bifidobacterium bifidum, Bifidobacterium longum, and Bifidobacterium longum subsp. infantis 30 billion colony-forming units (CFUs) twice daily for 7 days (90266). However, most other probiotic compounds containing L. acidophilus have not demonstrated benefit in most patients with constipation. One small clinical trial shows that taking yogurt 180 mL providing L. acidophilus NCFM, Bifidobacterium animalis subsp. lactis HN019, and polydextrose (Litesse) daily for 2 weeks modestly improves clinical response and reduces transit time when compared with taking a control yogurt. However, there was no effect on the number of daily bowel movements (90275). Other studies show that taking Lactobacillus acidophilus DDS-1 6.6 billion CFUs daily for 4 weeks in combination with Bifidobacterium longum UABl-14, Bifidobacterium animalis subsp. lactis UABla-12, Bifidobacterium bifidum UABb-10, and fructo-oligosaccharides (FOS) 7 mg does not improve symptoms of constipation when compared with a placebo providing FOS (110970). Also, there was a general lack of support for symptom improvement following the intake of Lactobacillus acidophilus NCFM 10 billion CFUs daily with Lacticaseibacillus paracasei Lpc-37 and Bifidobacterium animalis subsp. lactis strains Bl-04, Bi-07, and HN019 daily for 2 weeks (110979).
• Critical illness (trauma). Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in critically ill, hospitalized adults shows that taking L. acidophilus LA-5 1.75 billion colony-forming units (CFUs), Lactiplantibacillus plantarum 500 million CFUs, Bifidobacterium animalis subsp. lactis BB12 1.75 billion CFUs, and Saccharomyces boulardii 1.5 billion CFUs twice daily for 15 days modestly reduces the risk of sepsis, as well as the length of stay in the ICU and hospital, when compared with placebo (107524).
• Denture stomatitis. Although there has been interest in using oral Lactobacillus acidophilus for denture stomatitis, there is insufficient reliable information about the clinical effects of L. acidophilus for this condition.
• Depression. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with major depression shows that taking L. acidophilus, Lacticaseibacillus casei, and Bifidobacterium bifidum daily for 8 weeks reduces symptoms of depression measured on the Beck Depression Inventory (BDI) when compared with placebo (99780). However, the validity of the results from this study is limited by incomplete reporting. For example, patient baseline BDI scores were not reported.
• Diabetes. Oral Lactobacillus acidophilus in combination with other probiotic species seems to be beneficial for the treatment of gestational diabetes, although it is unclear if it is beneficial for treatment of type 1 or type 2 diabetes. Oral L. acidophilus is unlikely to be beneficial for the prevention of gestational diabetes. Details: Although some individual studies disagree, meta-analyses of clinical research in patients with gestational diabetes show that taking probiotics, most often L. acidophilus in combination with other species, improves glycemic indices such as fasting blood glucose and insulin sensitivity when compared with placebo (102288,104156). Also, one meta-analysis of clinical research shows that taking probiotics specifically containing L. acidophilus in combination with other species modestly improves these glycemic indices, as well as levels of total cholesterol and triglycerides, but not low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol (111796). Some doses used in available studies include a combination of freeze-dried L. acidophilus, Lacticaseibacillus casei, and Bifidobacterium bifidum each as 2 billion colony-forming units (CFUs) per gram daily for 6 weeks (95416,98430), a total of 4 billion CFUs of a combination of L. acidophilus LA-5, Bifidobacterium animalis subsp. lactis BB-12, Streptococcus thermophilus STY-31, and Lactobacillus delbrueckii subsp. bulgaricus LBY-27 for 8 weeks starting at 24-28 weeks' gestation (96892), and a specific product containing L. acidophilus and 7 other probiotics (Visbiome, ExeGi Pharma) as a total of 112.5 billion CFUs twice daily for 8 weeks (107549). Meta-analyses in patients with gestational diabetes show that taking probiotics such as L. acidophilus does not reduce the risk for caesarean section birth, neonatal hypoglycemia, large for gestational age birth, or hypertensive disorders such as pregnancy-induced hypertension, pre-eclampsia, or eclampsia (102288,104156,111796). However, one meta-analysis of clinical research shows that taking probiotics specifically containing L. acidophilus modestly reduces neonatal birth weight, but not maternal weight gain (111796). Taking L. acidophilus does not seem to be effective for PREVENTING gestational diabetes. A large clinical trial shows that taking L. acidophilus LA1 7.5 billion CFUs, Bifidobacterium longum sp54 cs 1.5 billion CFUs, and Bifidobacterium bifidum sp9 cs 6 billion CFUs daily from 14-24 weeks' gestation does not reduce the incidence of gestational diabetes when compared with taking placebo (107520). Research on the use of L. acidophilus for type 2 diabetes is mixed. Taking a combination of L. acidophilus, Bifidobacterium bifidum, and Streptococcus thermophilus daily for 12 weeks does not reduce levels of fasting blood glucose or glycated hemoglobin (HbA1c) when compared with placebo (107521). One clinical study shows that taking L. acidophilus along with six other probiotic strains (Familact) daily for 6 weeks reduces fasting blood glucose, but does not affect plasma insulin, when compared with placebo (99790). A small clinical trial shows that taking fermented goat milk 120 grams containing one billion CFUs each of L. acidophilus La-5 and Bifidobacterium animalis subsp. lactis BB-12 daily for 6 weeks modestly reduces levels of HbA1c and low-density lipoprotein (LDL) cholesterol, but not fasting blood glucose or insulin resistance, when compared with conventional fermented milk containing Streptococcus thermophilus TA-40 (110973). However, other clinical research shows that taking L. acidophilus 1 billion CFUs, along with Lacticaseibacillus rhamnosus, Bacillus coagulans GanedenBC30 (GBI-30, 6086), and fructo-oligosaccharides 500 mg daily for 12 weeks modestly reduces fasting blood glucose and insulin and improves measures of insulin resistance when compared with placebo (107731). Another clinical trial shows that taking yogurt 200 grams daily containing L. acidophilus 4.65 million CFUs per gram along with Bifidobacterium animalis subsp. lactis modestly reduces levels of HbA1c, triglyceride, and LDL cholesterol, but not fasting glucose, when compared with a placebo yogurt (111798). A combination probiotic containing L. acidophilus has also been evaluated in children 2-12 years of age with new-onset type 1 diabetes. One clinical study shows that taking a specific combination product (Visbiome, ExeGi Pharma) providing 112.5 billion CFUs daily for 3 months modestly decreases HbA1c and insulin requirements when compared with placebo. Also, about three times as many children achieved remission, defined as insulin requirements of less than 0.5 U/kg daily and HbA1c less than 7%. However, C-peptide levels and the maintenance of residual pancreatic beta-cell function were not affected when compared with placebo (107497).
• Diabetic nephropathy. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with diabetic nephropathy not taking antidiabetes drugs shows that taking a combination of L. acidophilus, Bifidobacterium bifidum, and Streptococcus thermophilus daily for 12 weeks modestly reduces the ratio of microalbuminuria/creatinine (mAlb/Cr), a marker of kidney damage, when compared with placebo. However, there was no effect on the estimated glomerular filtration rate (eGFR) (107521).
• Diarrhea. Oral heat-killed L. acidophilus seems to reduce the duration of diarrhea in adults and children. Oral live L. acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in children with dysentery being treated with ceftriaxone shows that taking a specific combination probiotic sachet (Kidilact, Zisttakhmir Company) containing live L. acidophilus, Lacticaseibacillus casei, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii subsp. bulgaricus, Bifidobacterium longum subsp. infantis, Bifidobacterium breve, and Streptococcus thermophilus daily for 5 days modestly reduces the duration of diarrhea, hospitalization, and blood in diarrhea when compared with control (102417). Heat-killed L. acidophilus has also been investigated for the treatment of diarrhea. A meta-analysis of four small clinical studies in infants and children ages 1 month to 4 years shows that taking heat-killed L. acidophilus LB 20-30 billion colony-forming units (CFUs) daily for up to 5 days along with oral or intravenous rehydration therapy can modestly reduce the duration of diarrhea, primarily of non-rotaviral origin (90295). Also, preliminary clinical research in patients with functional chronic diarrhea shows that taking heat-killed L. acidophilus LB (Lacteol Fort, Laboratoire du Lacteol du Dr Boucard) as two capsules twice daily for a total of 20 billion cells daily for 4 weeks reduces daily stool frequency by 3.5, compared with a reduction of 1.2 in patients taking five chewable capsules three times daily of an unspecified strain of L. acidophilus (Lacidophilin, Tai Ge Pharma Ltd). Stool consistency, pain, distention, and total efficacy, defined as a decrease in mean symptoms by at least 40%, were also further improved in patients taking the heat-killed product (107537). However, other clinical research in children ages 6 months to 12 years hospitalized with acute diarrhea shows that taking 15 billion heat-killed L. acidophilus (Lactrol, Raptakos) cells daily for 3 days along with oral rehydration solution (ORS) does not have beneficial effects on duration of diarrhea, frequency of stools, or length of hospital stay, when compared with ORS alone (111789). The European Society for Pediatric Infectious Diseases recommends probiotics in hospitalized children with diarrhea (98469) and the Infectious Disease Society of America (IDSA) recommends probiotics for the outpatient treatment of acute diarrhea (95388) However, L. acidophilus is not a specific focus of the guidelines and most evidence is low quality.
• Generalized anxiety disorder (GAD). Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients newly diagnosed with GAD shows that taking sertraline 25 mg plus probiotics daily for 8 weeks may modestly reduce some symptoms of anxiety when compared with sertraline alone. However, the reduction in anxiety score was small and change was not consistent between rating scales. Also, the quality of life was not improved. The probiotics provided a total of 18 billion colony-forming units of L. acidophilus, Bifidobacterium bifidum, Bifidobacterium longum, and Bifidobacterium animalis subsp. lactis (110977).
• Hepatic encephalopathy. Although there has been interest in using oral Lactobacillus acidophilus for hepatic encephalopathy, there is insufficient reliable information about the clinical effects of L. acidophilus for this condition.
• HIV/AIDS. Although there has been interest in using oral Lactobacillus acidophilus for HIV/AIDS, there is insufficient reliable information about the clinical effects of L. acidophilus for this condition.
• Hypercholesterolemia. It is unclear if oral Lactobacillus acidophilus is beneficial for lowering cholesterol levels; the available research is conflicting. Details: Two meta-analyses of clinical research show that taking fermented milk products containing L. acidophilus can reduce total cholesterol by about 14-19 mg/dL in adults with or without hypercholesterolemia. However, the effect of L. acidophilus on both total and LDL cholesterol levels is conflicting from available research (95396,95397,95399). Clinical trials included in these meta-analyses evaluated patients with hypercholesterolemia, type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), metabolic syndrome, and others. Taking L. acidophilus does not appear to improve high-density lipoprotein (HDL) cholesterol or triglyceride levels (95396,95397,95399). Doses used in some studies have included fermented milk products providing L. acidophilus 39 million to 2 billion CFUs daily, alone or along with other probiotic species, for up to 6 weeks (95396). One small clinical trial in patients with hypercholesterolemia shows that taking L. acidophilus LA-1 60 billion colony-forming units (CFUs) three times daily for 6 weeks does not affect serum lipids when compared with taking placebo (111791). A meta-analysis of nine small to moderate-sized clinical studies shows that taking a combination of L. acidophilus and Bifidobacterium animalis subsp. lactis reduces levels of total cholesterol when compared with placebo (107591). However, it is unclear if this is due to L. acidophilus, Bifidobacterium animalis subsp. lactis, or their combination.
• Hypertension. Although there has been interest in using oral Lactobacillus acidophilus for hypertension, there is insufficient reliable information about the clinical effects of L. acidophilus for this condition.
• Inflammatory bowel disease (IBD). Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small preliminary clinical trial in patients with collagenous colitis shows that taking 10 billion colony-forming units each of L. acidophilus LA-5 and Bifidobacterium longum subsp. lactis BB-12 twice daily for 12 weeks does not increase the proportion of patients with a reduction in weekly bowel frequency of at least 50% when compared with placebo. Also, there was no effect of this combination on stool consistency or abdominal symptoms. However, there were some modest benefits when compared with baseline (110999). This study was small and may have been underpowered to detect differences.
• Intraventricular hemorrhage. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in premature infants shows that taking 6 billion CFUs of a combination of L. acidophilus NCDO 1748 and Bifidobacterium bifidum NCDO 2203 (UFC Inforan, Switzerland) from 7 days of age until 34 weeks postmenstrual age or discharge does not reduce the odds of intraventricular hemorrhage when compared with a control group of infants not given these probiotics. The infants in this study were born at less than 32 weeks gestation and had a birthweight of less than 1500 grams (111794). This study is limited by the lack of randomization to treatment group; placement was based on year of birth.
• Lactose intolerance. It is unclear if oral Lactobacillus acidophilus is beneficial for lactose intolerance. Details: One small clinical trial shows that consuming 400 mL of a non-fermented milk product containing L. acidophilus 530 million colony-forming units (CFUs)/mL daily does not reduce symptoms of lactose intolerance or hydrogen breath test results when compared with milk without L. acidophilus (16737). Another small preliminary clinical trial shows that taking L. acidophilus BG2FO4 10 billion CFUs twice daily for 7 days does not reduce lactose-induced gastrointestinal symptoms or improve lactose digestion based on breath hydrogen when compared with baseline (111783). However, another clinical trial shows that adding various L. acidophilus strains 800 million to 1 billion CFUs/mL to non-fermented milk improves hydrogen breath tests in patients with lactose intolerance (16738).
• Lyme disease. Although there has been interest in using oral Lactobacillus acidophilus for Lyme disease, there is insufficient reliable information about the clinical effects of L. acidophilus for this condition.
• Metabolic syndrome. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in elderly patients with metabolic syndrome shows that taking a combination of L. acidophilus PBS066-DSM 24,936, Lactiplantibacillus plantarum PBS067-DSM 24,937, and Limosilactobacillus reuteri PBS072-DSM 25,175 as 2 billion colony-forming units (CFUs) each, with inulin and fructo-oligosaccharides daily for 60 days, reduces the number of patients diagnosed with metabolic syndrome by 23%, compared with a 10% reduction in those taking placebo. In the probiotic group, there were modest improvements in waist circumference and levels of fasting plasma insulin, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and inflammatory mediators when compared with placebo. However, there were no significant differences between groups for fasting blood glucose or blood pressure. All patients in this study were on a Mediterranean-like standard diet (107560).
• Necrotizing enterocolitis (NEC). It is unclear if oral Lactobacillus acidophilus is beneficial or safe for NEC prevention. Details: Most meta-analyses of clinical research show that giving lactobacilli enterally reduces the risk of NEC and/or severe NEC in preterm, mainly very low birth weight (VLBW), infants. Some meta-analyses support the use of lactobacilli in combination with bifidobacteria, as opposed to lactobacilli alone for reducing the risk of NEC. However, only a small number of the individual studies included in these analyses have investigated the effects of L. acidophilus, which was used as part of a combination probiotic and/or prebiotic product in all cases (95344,95351,103437,103445,104157,105162,105164). Also, guidance among regulatory agencies and clinical organizations varies with respect to the use of probiotics in very low birth weight infants under 1000 grams. The US Food and Drug Administration (FDA) warns that preterm infants given probiotics are at risk of serious infections caused by the bacteria or fungi contained in probiotics due to cases reported in this group of infants (111610). Also, The American Academy of Pediatrics does not support the routine administration of probiotics to preterm infants, particularly those with a birth weight below 1000 grams, due to conflicting data on safety and efficacy and potential for harm in this vulnerable population (111608). The Canadian Paediatric Society, the American Gastroenterological Association, and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition state that probiotic combinations may be of benefit in reducing the incidence of NEC in preterm neonates over 1000 grams. However, L. acidophilus is not specifically recommended (103003,111609,111611).
• Nonalcoholic fatty liver disease (NAFLD). Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In children with NAFLD, clinical research shows that taking a specific combination product (Prokid, Gostaresh Milad Pouya Company) containing L. acidophilus ATCC B3208 3 billion colony-forming units (CFUs), Lacticaseibacillus rhamnosus DSMZ 21690 2 billion CFUs, Bifidobacterium animalis subsp. lactis DSMZ 32269 6 billion CFUs, and Bifidobacterium bifidum ATCC SD6576 2 billion CFUs daily for 12 weeks normalizes liver sonography findings in 53% of children, compared with 17% of those taking placebo. In addition, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are reduced by 30% and 25%, respectively. There was no effect on body mass index or blood lipids when compared with placebo (105156). Another clinical trial shows that taking two sachets daily for 3 months of a specific combination product (VSL#3) containing L. acidophilus and other probiotics modestly decreases triglyceride levels and liver enzymes when compared with taking placebo. However, there was no change in body mass index or most glycemic or lipid parameters (111009). However, taking L. acidophilus in combination with other probiotics does not seem to be beneficial in adults with NAFLD. Clinical research shows that taking yogurt 100 grams, containing L. acidophilus La-5 and Bifidobacterium animalis subsp. lactis Bb-12 40 million CFUs and vitamin D 1000 IU, daily for 3 months does not improve fasting blood glucose levels, insulin levels, blood pressure, or anthropometric indices when compared with unfortified yogurt (105174). Also, a small clinical trial shows that taking a combination of L. acidophilus BCMC 12,130, Lacticaseibacillus casei BCMC 12,313, Lactobacillus delbrueckii subsp. lactis BCMC 12,451, Bifidobacterium bifidum BCMC 02290, Bifidobacterium longum subsp. infantis BCMC 02129, and Bifidobacterium longum BCMC 02120 30 billion colony-forming units twice daily for 6 months has no beneficial effects on hepatic steatosis or fibrosis or on levels of liver enzymes, blood lipids, or fasting glucose, when compared with placebo (107523).
• Nonalcoholic steatohepatitis (NASH). Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with NASH shows that taking 1 billion colony-forming units each of L. acidophilus ATCC SD5221 and Bifidobacterium animalis subsp. lactis HN019 daily for 6 months does not have beneficial effects on severity of liver fibrosis or steatosis, metabolic markers, or inflammation when compared with taking placebo. The effect of this combination on liver enzymes was mixed (111797).
• Obesity. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In combination with Bifidobacterium animalis subsp. lactis BS01, taking L. acidophilus LA02 2 billion colony-forming units (CFUs) daily for 6 weeks does not reduce body weight or body fat when compared with placebo in young, healthy females, only some of whom were overweight (103438). However, another clinical study shows that taking 50 billion CFUs of a specific combination of L. acidophilus, Lactiplantibacillus plantarum, Bifidobacterium bifidum, and B. animalis subsp. lactis (Lab4P) for 24 weeks reduces body weight by an additional 1.3 kg more than placebo (103439).
• Polycystic ovary syndrome (PCOS). Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients with PCOS, clinical research shows that taking a combination of L. acidophilus T16 (IBRC-M10785), Lacticaseibacillus casei T2 (IBRC-M10783), and Bifidobacterium bifidum T1 (IBRC-M10771) 2 billion colony-forming units each, plus inulin 800 mg, daily for 12 weeks modestly reduces serum insulin and triglyceride levels and improves insulin resistance and insulin sensitivity when compared with placebo. However, it does not alter cholesterol or fasting glucose levels (105159). Another clinical trial shows that 31.3% of patients with PCOS taking L. acidophilus in combination with other probiotics daily for 6 months had regular menstrual cycles compared with 12.5% of those taking placebo. There were also modest improvements in testosterone levels and waist circumference, but not other hormones, insulin resistance, body weight, or most measures of quality of life. The product provided Lactobacillus acidophilus UBLA-34 2 billion CFUs along with Bifidobacterium bifidum UBBB-55, Lactiplantibacillus plantarum UBLP-40, Lacticaseibacillus casei UBLC-42, Limosilactobacillus fermentum UBLF-31, Lacticaseibacillus rhamnosus UBLR-58, Limosilactobacillus reuteri UBLRu-87, and fructo-oligosaccharides (FOS) daily for 2 months and then twice daily for 4 months. All patients also underwent dietary and lifestyle changes (110974).
• Postoperative infection. Although there has been interest in using oral Lactobacillus acidophilus for preventing postoperative infections, there is insufficient reliable information about the clinical effects of lactobacillus for this purpose.
• Pouchitis. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Continuous oral treatment for one year with a specific concentrated formulation of L. acidophilus and other probiotics (Visbiome, ExeGi Pharma) as 6 grams (300-500 billion live bacteria per gram), daily for up 12 months seems to maintain remission of pouchitis in 85% of patients (6087,12769). Also, one small clinical study shows that taking a specific product (Trilac, Allergon AB) containing L. acidophilus 600 million colony-forming units (CFUs) per capsule, Lactobacillus delbrueckii subsp. bulgaricus 400 million CFUs per capsule, and Bifidobacterium bifidum 600 million CFUs per capsule, taken in doses of two capsules three times daily for 9 months, can reduce pouchitis severity and the number of patients experiencing pouchitis when compared to baseline (90296). The validity of these findings is limited by the lack of a comparator group.
• Pregnancy-induced nausea and vomiting. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small preliminary clinical trial shows that taking probiotics during pregnancy reduces the severity and duration of nausea and vomiting by 16% to 54%. There was also a small benefit on stool hardness. A specific probiotic (Probiotics 10, Nature's Bounty) was taken as 2 capsules daily for two back-to-back cycles of six days with probiotics and two days without. Each capsule contained a total of 10 billion colony-forming units (CFUs) of L. acidophilus La-14, Lactiplantibacillus plantarum 299v and DSM 15312, Lactobacillus delbrueckii subsp. bulgaricus Lb-87, Lacticaseibacillus paracasei DSM 13434 and Lpc-37, Ligilactobacillus salivarius Ls-33, Levilactobacillus brevis Lbr-35, Lacticaseibacillus casei Lc-11, and Bifidobacterium animalis subsp. lactis Bl-04, along with inulin 200 mg (107199).
• Prematurity. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In premature infants, clinical research shows that taking a blend of L. acidophilus, bifidobacteria, and Enterococcus faecalis (Peifeikang powder, Shanghai Xinyi Pharmaceutical Company), at least 5 million colony-forming units (CFUs) three times daily from birth until implementation of total parenteral nutrition, reduces the rate of development of extrauterine growth retardation from 15% to 8% when compared with those not receiving this blend (103448). Other preliminary clinical research in premature infants shows that taking 6 billion CFUs of a combination of L. acidophilus NCDO 1748 and Bifidobacterium bifidum NCDO 2203 (UFC Inforan, Switzerland) from 7 days of age until 34 weeks postmenstrual age or discharge reduces the odds of neurodevelopment impairment at 24 months corrected age by 70% when compared with a control group of infants not given these probiotics. The odds of having moderate to severe impairment were also reduced. The infants in this study were born at less than 32 weeks gestation and had a birthweight of less than 1500 grams (111794). This study is limited by the lack of randomization to treatment group; placement was based on year of birth. Observational research has also been conducted. One large observational study in infants fed strictly human milk, but not strictly formula or a combination, suggests that taking L. acidophilus 1 to 3 billion CFUs with Bifidobacterium longum subsp. infantis during the first month of life for the prevention of necrotizing enterocolitis was associated with a modest increased weight gain velocity. The infants in this study were born between 22-29 weeks gestation and had a birthweight of less than 1500 grams (111771).
• Psoriasis. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with psoriasis shows that taking a mixture of probiotics for 8 weeks modestly improves overall symptoms and feelings of depression when compared with placebo. The percentage of patients achieving at least a 50% or 75% reduction in overall symptom score was 40% and 24%, respectively, in those taking the probiotic mixture, compared with 16% and 8% of those taking placebo. Each probiotic capsule was used twice daily and provided a total daily dose of 2.6 billion colony-forming units (CFUs) of L. acidophilus, Bifidobacterium bifidum, Bifidobacterium animalis subsp. lactis, and Bifidobacterium longum (107498).
• Radiation-induced diarrhea. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with cervical cancer receiving radiotherapy with or without chemotherapy shows that taking a specific product (Biogurt, Fame Pharmaceuticals) containing L. acidophilus LA-5 and Bifidobacterium animalis subsp. lactis BB-12 as 1.75 billion lyophilized colony-forming units (CFUs) as a capsule three times daily throughout treatment reduces the risk of diarrhea by 28% when compared with placebo. The treatment group also used less loperamide (102285). Another small clinical trial in patients undergoing pelvic radiotherapy with weekly cisplatin shows that taking L. acidophilus and Bifidobacterium bifidum (Infloran, Laboratio Farmaceutico SIT) as 1 billion CFUs each, twice daily from seven days before starting radiotherapy and continuing during radiotherapy, reduces the incidence of moderate to severe diarrhea and the need for antidiarrheal medication when compared with placebo. Moderate to severe diarrhea occurred in 9% of patients using the probiotics, compared with 45% of those taking placebo (107580).
• Respiratory tract infections. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in children ages 3-5 years who attend daycare centers shows that taking a combination milk product containing 5 billion colony-forming units (CFUs) each of L. acidophilus and Bifidobacterium animalis (HOWARU Protect, Danisco) reduces the risk of experiencing fever, cough, and rhinorrhea by 45% when compared with placebo. Patients taking this combination experienced an average 2-day shorter duration of symptoms and were significantly less likely to use an antibiotic for their symptoms. Patients who took L. acidophilus without bifidobacterium also had a reduction in fever, cough, and use of antibiotics, but not rhinorrhea (16847). In healthy children aged 3-10 years, clinical research shows that taking 12.5 billion CFUs daily of a specific combination of L. acidophilus CUL21 and CUL60, Bifidobacterium bifidum CUL20, Bifidobacterium animalis subsp. lactis CUL34 (Lab4), and vitamin C 50 mg daily reduces the risk of cough by 16% and sore throat by 20%, and modestly reduces school absenteeism and antibiotic use when compared with placebo. However, nasal symptoms, fever, and wheezing were not reduced (106943). A different combination product containing L. acidophilus DDS-1 1 billion CFUs and B. animalis subsp. lactis UABLA-12 4 billion CFUs (Up4-Junior, UAS Laboratories) with fructo-oligosaccharides 50 mg has also been evaluated. Clinical research in children 3-12 years of age with a sick household member shows that taking this product daily for 2 weeks modestly shortens the duration of respiratory infections, but does not reduce the risk of developing an infection, when compared with placebo (98439). In overweight adults or adults with obesity, taking 50 billion CFUs of a specific combination of L. acidophilus, Lactiplantibacillus plantarum, B. bifidum, and B. animalis subsp. lactis (Lab4P) for 24 weeks reduces the overall likelihood of having upper respiratory tract infection symptoms, such as sneezing, cough, and blocked nose, by approximately 40% when compared with placebo (103439).
• Retinopathy of prematurity. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in premature infants shows that taking 6 billion CFUs of a combination of L. acidophilus NCDO 1748 and Bifidobacterium bifidum NCDO 2203 (UFC Inforan, Switzerland) from 7 days of age until 34 weeks postmenstrual age or discharge does not reduce the odds of retinopathy of prematurity when compared with a control group of infants not given these probiotics. The infants in this study were born at less than 32 weeks gestation and had a birthweight of less than 1500 grams (111794). This study is limited by the lack of randomization to treatment group; placement was based on year of birth. Also, one large observational study in premature infants suggests that taking L. acidophilus 1 to 3 billion CFUs with Bifidobacterium longum subsp. infantis during the first month of life for the prevention of necrotizing enterocolitis was not associated with a reduced risk of retinopathy of prematurity. The infants in this study were born between 22-29 weeks gestation and had a birthweight of less than 1500 grams (111771).
• Rheumatoid arthritis (RA). Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with moderate-to-severe RA shows that taking capsules containing freeze-dried strains of L. acidophilus, Lacticaseibacillus casei, and Bifidobacterium bifidum daily for 8 weeks does not improve RA severity, the number of tender or swollen joints, or joint pain when compared with placebo (95418).
• Rotaviral diarrhea. It is unclear if oral Lactobacillus acidophilus is beneficial for rotaviral diarrhea. Details: One preliminary clinical study shows that taking a combination of L. acidophilus AD031 2 billion colony-forming units (CFUs) and Bifidobacterium longum BORI 20 billion CFUs twice daily for 3 days reduces the duration of rotaviral diarrhea by an average of 3 days when compared with placebo (95334). However, one clinical study using a lower dose and different strain of L. acidophilus (La-14) 200 million CFUs twice daily for 5 days shows that this regimen does not reduce the duration of watery diarrhea or affect the viral load in children aged 9 months to 5 years with confirmed norovirus or rotavirus infection (96887). A small clinical study shows that heat-killed L. acidophilus LB 20-30 billion cells daily for up to 4 days can modestly reduce the duration of diarrhea in infants and children, some of which had confirmed rotavirus (90295).
• Sepsis. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in premature infants shows that taking 6 billion CFUs of a combination of L. acidophilus NCDO 1748 with Bifidobacterium bifidum NCDO 2203 (UFC Inforan, Switzerland) from 7 days of age until 34 weeks postmenstrual age or discharge reduces the odds of late onset sepsis by 55% when compared with a control group of infants not given these probiotics. The infants in this study were born at less than 32 weeks gestation and had a birthweight of less than 1500 grams (111794). This study is limited by the lack of randomization to treatment group; placement was based on year of birth. One large observational study in infants fed a mix of human milk and formula, but not strictly human milk or formula, suggests that taking L. acidophilus 1 to 3 billion CFUs with Bifidobacterium longum subsp. infantis during the first month of life for the prevention of necrotizing enterocolitis was associated with a 31% reduction in the development of clinical sepsis. The infants in this study were born between 22-29 weeks gestation and had a birthweight of less than 1500 grams (111771).
• Short bowel syndrome. Although there has been interest in using oral Lactobacillus acidophilus for short bowel syndrome, there is insufficient reliable information about the clinical effects of lactobacillus for this condition.
• Small intestinal bacterial overgrowth (SIBO). Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in children with chronic diarrhea due to SIBO shows that taking a combination of lyophilized L. acidophilus 1.5 grams and Lacticaseibacillus casei 1.5 grams by mouth twice daily for 21 days decreases average daily stools by 1.5, but does not improve other symptoms, when compared with placebo (91143). Also, one preliminary clinical study shows that taking a total of 2 billion CFUs of L. acidophilus and Lacticaseibacillus rhamnosus (Lacidofil) daily for 4 weeks does not prevent the development of SIBO in children that started treatment with omeprazole 20 mg daily for epigastric pain (90262).
• Travelers' diarrhea. It is unclear if oral Lactobacillus acidophilus is beneficial for the prevention of travelers' diarrhea. Details: A meta-analysis which included three clinical studies evaluating the use of L. acidophilus in adults traveling to different parts of the world found no benefit for the prevention of travelers' diarrhea when compared with placebo (101445). The effectiveness of this species may vary significantly based upon the destination of travel. Destinations in the same country can have different results, probably due to differences in bacteria and other microorganisms at different locations (10216).
• Ulcerative colitis. Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: The best evidence of benefit is for a specific combination product (Visbiome, ExeGi Pharma). Doses of 3 grams (equivalent to 900 billion colony-forming units (CFUs)) once or twice daily have been used in combination with conventional treatment. In children aged 1-16 years, doses of 450-1800 billion CFUs for up to one year have been used (3261,14370,14371,16841,95337). A meta-analysis of clinical research shows that taking this product as an adjunct to standard ulcerative colitis treatment can increase remission rates in adults and children by about 1.7-fold when compared with standard treatment alone (95337). Preliminary clinical research in patients with moderate to severe symptoms taking mesalazine 1200 mg daily shows that taking an unknown dose of L. acidophilus twice daily along with Bifidobacterium bifidum BGN4 and Ligilactobacillus salivarius (Acronelle, Bromatech srl, Milan, Italy) for 2 years modestly improves patient- and physician-scales of overall symptoms when compared with taking mesalazine alone. There were also improvements in stool frequency and rectal bleeding (110981). Although some contradictory evidence exists (3261,16841), most research shows that taking Visbiome or a combination of L. acidophilus LA-5 and Bifidobacterium animalis subsp. lactis BB-12 (Probio-Tec AB-25) does not prevent relapse in people who are already in remission (95337,95338).
• Urinary tract infections (UTIs). Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In children aged 4 months to 5 years with a previous UTI, clinical research shows that taking a specific combination of L. acidophilus, Lacticaseibacillus rhamnosus, Bifidobacterium bifidum, and Bifidobacterium animalis subsp. lactis (Complete Probiotic Platinum) for 18 months increases the median time to the first incidence of recurrence by approximately 3 months and increases the percentage of children without a UTI during the study period from 83% to 97% (103436).
• Vaginal candidiasis. It is unclear if oral or intravaginal Lactobacillus acidophilus is beneficial for vaginal candidiasis. Details: In a small preliminary clinical trial in patients with recurrent vulvovaginal candidiasis who had undergone a week of oral fluconazole treatment followed by intravaginal L. acidophilus LA 02 and Limosilactobacillus fermentum LF10, 72.4% of patients demonstrated a lack of clinical recurrence over a 7 month observational period. All patients took fluconazole 200 mg three times in the first week followed by intravaginal application with at least 0.4 billion colony-forming units each of L. acidophilus LA 02 and Limosilactobacillus fermentum LF10, along with arabinogalactan and fructo-oligosaccharides (FOS) on alternate days for 10 days and then once weekly for 10 weeks (111781). However, a combination of L. acidophilus, Lacticaseibacillus rhamnosus, Lactobacillus delbrueckii, and Streptococcus thermophilus (Femilac) given intravaginally, does not seem to reduce the risk of vaginal candidiasis infection following use of antibiotics (12108). There is also some evidence that eating yogurt enriched with L. acidophilus daily does not reduce the risk of recurrent vaginal candidiasis (1245).
• Ventilator-associated pneumonia (VAP). Oral Lactobacillus acidophilus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking L. acidophilus LA-5 1.75 billion colony-forming units (CFUs), Lactiplantibacillus plantarum 500 million CFUs, Bifidobacterium animalis subsp. lactis BB12 1.75 billion CFUs, and Saccharomyces boulardii 1.5 billion CFUs twice daily for 15 days reduces the risk of VAP to 12%, compared with 28% in those taking placebo. Half of the dose was given onto the oropharynx and half via a nasogastric tube (107524). More evidence is needed to rate Lactobacillus acidophilus for these uses.

(Read more about LACTOBACILLUS ACIDOPHILUS)

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.

(Read more about PHYTASE)

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))

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

POSSIBLY SAFE ...when black pepper oil is applied topically. Black pepper oil is nonirritating to the skin and is generally well tolerated (11). ...when black pepper oil is inhaled through the nose or as a vapor through the mouth, short-term. Black pepper oil as a vapor or as an olfactory stimulant has been used with apparent safety in clinical studies for up to 3 days and 30 days, respectively (29159,29160,29161,90502). There is insufficient reliable information available about the safety of black pepper when used orally in medicinal amounts.

CHILDREN: LIKELY SAFE
when used orally in amounts commonly found in foods (11).

CHILDREN: POSSIBLY UNSAFE
when used orally in large amounts. Fatal cases of pepper aspiration have been reported in some patients (5619,5620). There is insufficient reliable information available about the safety of topical pepper oil when used in children.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods (11).

PREGNANCY: LIKELY UNSAFE
when used orally in large amounts. Black pepper might have abortifacient effects (11,19); contraindicated. There is insufficient reliable information available about the safety of topical pepper when used during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (11). There is insufficient reliable information available about the safety of black pepper when used in medicinal amounts during breast-feeding.

(Read more about BLACK PEPPER)

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)

LIKELY SAFE ...when used orally and appropriately. Lactobacillus acidophilus has been safely used as part of multi-ingredient probiotic products in studies lasting up to nine months (1731,6087,14370,14371,90231,90296,92255,103438,12775,107581)(110950,110970,110979,110998,111785,111793). ...when used intravaginally and appropriately. L. acidophilus has been used safely in studies lasting up to 12 weeks (12108,13176,13177,90265). There is insufficient reliable information available about the safety of non-viable, heat-killed L. acidophilus formulations when used orally.

CHILDREN: LIKELY SAFE
when used orally and appropriately in children of most ages. Lactobacillus acidophilus has been safely used for up to 5 days (96887). Also, combination probiotics containing L. acidophilus have been used with apparent safety in various doses and durations. L. acidophilus has been combined with Bifidobacterium animalis (HOWARU Protect, Danisco) for up to 6 months in children 3-5 years old (16847), with Bifidobacterium bifidum for 6 weeks (90602,96890), with Bifidobacterium bifidum and Bifidobacterium animalis subsp. lactis (Complete Probiotic Platinum) for 18 months in children 4 months to 5 years of age (103436), and in a specific product (Visbiome, ExeGi Pharma) containing a total of 8 species for 3 months in children 2-12 years old (107497). There is insufficient reliable information available about the safety of L. acidophilus in preterm infants with a birth weight under 1000 grams. 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: POSSIBLY SAFE
when used orally and appropriately. A combination of Lactobacillus acidophilus, Lacticaseibacillus casei, and Bifidobacterium bifidum has been used with apparent safety for 6 weeks, starting at 24-28 weeks' gestation (95416,98430).

LACTATION:
There is insufficient reliable information available about the safety of Lactobacillus acidophilus during lactation. However, there are currently no reasons to expect safety concerns when used appropriately.

(Read more about LACTOBACILLUS ACIDOPHILUS)

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.

(Read more about LIPASE)

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.

(Read more about PHYTASE)

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.

(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

AMOXICILLIN (Amoxil, Trimox) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the effects and side effects of amoxicillin.  Details Animal research shows that taking piperine, a constituent of black pepper, with amoxicillin increases plasma levels of amoxicillin (29269). This has not been reported in humans.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the risk of bleeding when taken with antiplatelet or anticoagulant drugs.  Details In vitro research shows that piperine, a constituent of black pepper, seems to inhibit platelet aggregation (29206). This has not been reported in humans.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Animal research shows that piperine, a constituent of black pepper, can reduce blood glucose levels (29225). Monitor blood glucose levels closely. Dose adjustments might be necessary.

ATORVASTATIN (Lipitor) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase blood levels of atorvastatin.  Details Animal research shows that taking piperine, a constituent of black pepper, 35 mg/kg can increase the maximum serum concentration of atorvastatin three-fold (104188). This has not been reported in humans.

CARBAMAZEPINE (Tegretol) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, black pepper might increase blood levels of carbamazepine, potentially increasing the effects and side effects of carbamazepine.  Details One clinical study in patients taking carbamazepine 300 mg or 500 mg twice daily shows that taking a single 20 mg dose of purified piperine, a constituent of black pepper, increases carbamazepine levels. Piperine may increase carbamazepine absorption by increasing blood flow to the GI tract, increasing the surface area of the small intestine, or inhibiting cytochrome P450 3A4 (CYP3A4) in the gut wall. Absorption was significantly increased by 7-10 mcg/mL/hour. The time to eliminate carbamazepine was also increased by 4-8 hours. Although carbamazepine levels were increased, this did not appear to increase side effects (16833). In vitro research also shows that piperine can increase carbamazepine levels by 11% in a time-dependent manner (103819).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the effects and side effects of cyclosporine.  Details In vitro research shows that piperine, a constituent of black pepper, increases the bioavailability of cyclosporine (29282). This has not been reported in humans.

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP1A1.  Details In vitro research suggests that piperine, a constituent of black pepper, inhibits CYP1A1 (29213). This has not been reported in humans.

CYTOCHROME P450 2B1 (CYP2B1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP2B1.  Details In vitro research suggests that piperine, a constituent of black pepper, inhibits CYP2B1 (29332). This has not been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP2D6.  Details In vitro research suggests that some constituents of black pepper inhibit CYP2D6 (29207,29212,38375). This has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of drugs metabolized by CYP3A4.  Details In vitro research shows that piperine, a constituent of black pepper, as well as the pepper fruit seem to inhibit CYP3A4 (14375,29212). This has not been reported in humans.

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, black pepper might increase blood levels of lithium due to its diuretic effects. The dose of lithium might need to be reduced.  Details Black pepper is thought to have diuretic properties (11).

NEVIRAPINE (Viramune) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Black pepper might increase blood levels of nevirapine.  Details Clinical research shows that piperine, a constituent of black pepper, increases the plasma concentration of nevirapine. However, no adverse effects were observed in this study (29209).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase levels of P-glycoprotein substrates.  Details In vitro research shows that piperine, a constituent of black pepper, seems to inhibit P-glycoprotein (14375,29281,29283).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, black pepper might increase the sedative effects of pentobarbital.  Details Animal research shows that piperine, a constituent of black pepper, increases pentobarbital-induced sleeping time (29214).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of phenytoin.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption, slow elimination, and increase levels of phenytoin (537,14442). Taking a single dose of black pepper 1 gram along with phenytoin seems to double the serum concentration of phenytoin (14375). Consuming a soup with black pepper providing piperine 44 mg/200 mL of soup along with phenytoin also seems to increase phenytoin levels when compared with consuming the same soup without black pepper (14442).

PROPRANOLOL (Inderal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of propranolol.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and slow elimination of propranolol (538).

RIFAMPIN (Rifadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Black pepper might increase blood levels of rifampin.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and serum levels of rifampin (14375,29284).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Black pepper might increase blood levels of theophylline.  Details Clinical research shows that piperine, a constituent of black pepper, seems to increase absorption and slow elimination of theophylline (538).

(Read more about BLACK PEPPER)

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).

(Read more about BROMELAIN)

(Read more about FRUCTO-OLIGOSACCHARIDES (FOS))

(Read more about LACTASE)

ANTIBIOTIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking Lactobacillus acidophilus with antibiotic drugs might decrease the effectiveness of L. acidophilus.  Details L. acidophilus preparations usually contain live and active organisms. Therefore, simultaneously taking antibiotics might kill a significant number of the organisms (1740). Tell patients to separate administration of antibiotics and L. acidophilus preparations by at least two hours.

(Read more about LACTOBACILLUS ACIDOPHILUS)

(Read more about LIPASE)

(Read more about PHYTASE)

(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

General ...Orally, black pepper seems to be well tolerated when used in the amounts found in food or when taken as a medicine as a single dose. Topically and as aromatherapy, black pepper oil seems to be well tolerated.
Most Common Adverse Effects:
Orally: Burning aftertaste, dyspepsia, and reduced taste perception.
Inhalation: Cough.
Serious Adverse Effects (Rare):
Orally: Allergic reaction in sensitive individuals.

Gastrointestinal ...Orally, black pepper can cause a burning aftertaste (5619) and dyspepsia (38061). Single and repeated application of piperine, the active constituent in black pepper, to the tongue and oral cavity can decrease taste perception (29267). By intragastric route, black pepper 1.5 grams has been reported to cause gastrointestinal microbleeds (29164). It is not clear if such an effect would occur with oral administration.

Immunologic ...In one case report, a 17-month-old male developed hives, red eyes, facial swelling, and a severe cough following consumption of a sauce containing multiple ingredients. Allergen skin tests were positive to both black pepper and cayenne, which were found in the sauce (93947).

Ocular/Otic ...Topically, ground black pepper can cause redness of the eyes and swelling of the eyelids (5619).

Pulmonary/Respiratory ...When inhaled through the nose as an olfactory stimulant, black pepper oil has been reported to cause cough in one clinical trial (29162).

(Read more about BLACK PEPPER)

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).

(Read more about BROMELAIN)

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).

(Read more about FRUCTO-OLIGOSACCHARIDES (FOS))

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).

(Read more about LACTASE)

General ...Orally and intravaginally, Lactobacillus acidophilus is generally well tolerated.
Most Common Adverse Effects:
Orally: Mild gastrointestinal adverse effects.
Intravaginally: Vaginal discharge.
Serious Adverse Effects (Rare):
Orally: There is concern that L. acidophilus may cause infections in some people.

Dermatologic ...Orally, in one clinical trial, a combination of Lactobacillus acidophilus La-5, Lacticaseibacillus paracasei subsp. paracasei F19, and Bifidobacterium animalis subsp. lacltis BB-12 was associated with two cases of rash, one with itching. However, it is not clear if these adverse effects were due to L. acidophilus, other ingredients, the combination, or if the events were idiosyncratic (90236).

Gastrointestinal ...Orally, taking Lactobacillus acidophilus in combination with other probiotics may cause gastrointestinal side effects including epigastric discomfort (90239), abdominal pain (90239,90291,111785), dyspepsia (90239), flatulence (107497,107520), bloating (107497,111785), diarrhea (111785), vomiting (107537), and burping (90239); however, these events are uncommon.

Genitourinary ...Intravaginally, cream containing Lactobacillus acidophilus has been shown to cause increased vaginal discharge in about 5% of patients, compared to about 1% of patients receiving placebo cream (90237). Vaginal burning was reported by one person using intravaginal L. acidophilus and Limosilactobacillus fermentum in a clinical trial (111781).

Immunologic ...Since Lactobacillus acidophilus preparations contain live and active microorganisms, there is some concern that they might cause pathogenic infection in some patients. L. acidophilus has been isolated in some cases of bacteremia, sepsis, splenic abscess, liver abscess, endocarditis, necrotizing fasciitis, pancreatic necrosis, and meningoencephalitis. Most of these cases are thought to be due to the translocation of bacteria from other locations in the body in which they occur naturally, such as the oral cavity and gastrointestinal tract (107543,111782,111792). L. acidophilus endophthalmitis has been reported rarely (111787,111795). In one case, it was related to intravitreal injections for age-related macular degeneration in a 90-year-old female with an intraocular lens (111787). In another, it occurred following cataract surgery (111795).

(Read more about LACTOBACILLUS ACIDOPHILUS)

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).

(Read more about LIPASE)

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).

(Read more about PHYTASE)

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).

(Read more about PROTEOLYTIC ENZYMES (PROTEASES))