Zymex II [Discontinued] by SP Standard Process

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. However, 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 (6252,91104,91106,99467,99477,103299). 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 (6252,91104,99467,99477). 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 aftersome oral surgeries. 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). 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). Additionally, a small clinical study in patients undergoing crown lengthening dental surgeries with either minimal or no bone surgery shows that taking bromelain 200 mg 1 hour before surgery and every 6 hours after surgery reduces pain during the 48-hour postoperative period similarly to ibuprofen 400 mg taken on the same schedule(113898). 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

• Atopic dermatitis (eczema). It is unclear if topical fig fruit extract is beneficial in children with eczema. Details: Preliminary clinical research in children 4 months to 14 years of age with mild to moderate atopic dermatitis shows that topical application of a cream containing fig fruit extract 8% twice daily for 14 days reduces the severity of symptoms by 56% and itchiness by 64% when compared with baseline. Fig cream is as effective as a cream containing 1% hydrocortisone and more effective than placebo (99958).
• Constipation. It is unclear if oral fig fruit is beneficial for constipation. Details: A small clinical study in adults with constipation shows that taking fig fruit paste 300 grams daily for 8 weeks improves stool consistency by 58%, compared to a 27% improvement with placebo. Fig paste also modestly improves abdominal discomfort; however, it does not affect stool frequency, abdominal pain, effort, or relief (99956).
• Diabetes. It is unclear if oral fig leaf is beneficial for glycemic control in patients with type 1 diabetes. Details: A very small clinical crossover study in adults with type 1 diabetes shows that consuming a tea made from fig leaves modestly reduces postprandial, but not pre-prandial, glucose levels and also reduces insulin requirements when compared with consuming a non-fig tea (12578).
• Vitiligo. Although there has been interest in using oral fig for vitiligo, there is insufficient reliable information about the clinical effects of fig for this condition.
• Warts. It is unclear if topical fig latex is beneficial for warts in adults and children. Details: Preliminary clinical research in adults and children 5 years of age and older shows that applying fig latex directly to a common wart three times daily for at least 4 days is slightly less effective than cryotherapy for producing complete resolution of the wart after 2 weeks (99962).
• Wound healing. Although there has been interest in using topical fig for wound healing, there is insufficient reliable information about the clinical effects of fig for this purpose. More evidence is needed to rate fig for these uses.

(Read more about FIG)

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

• Cancer. Although there has been interest in using oral papain for cancer, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Dental caries. It is unclear if topical papain gel is beneficial for reducing procedure time or pain in children having caries removed by a dentist. Details: A small clinical study in children 3-9 years of age with dental caries shows that application of a specific papain gel (Brix3000, Brix Medical Science) 3000 U/mg during atraumatic restorative treatment (ART) by a dentist actually increases the time required to remove caries tissue, with no effect on pain, when compared with ART alone (107434).
• Diabetic foot ulcers. Although there has been interest in using topical papain for diabetic foot ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Exercise-induced muscle soreness. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy males shows that taking a combination enzyme tablet containing papain 50 mg, trypsin 75 mg, bromelain 50 mg, amylase 10 mg, lipase 10 mg, lysosome 10 mg, and chymotrypsin 2 mg, four times in one day before downhill running, improves recovery of contractile muscle function and decreases muscle soreness when compared with placebo (67838). It is unclear if these findings are due to papain, other ingredients, or the combination.
• Herpes zoster (shingles). Although there has been interest in using oral papain for shingles, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Insect bite. It is unclear if topical papain is beneficial in individuals with fire ant stings. Details: A small clinical study in individuals with fire ant stings shows that applying gauze soaked with a specific papain-containing meat tenderizer (Adolph's meat tenderizer) to the sting for 20 minutes does not reduce pain or itching when compared with placebo (67845).
• Intestinal parasite infection. Although there has been interest in using oral papain for intestinal parasite infections, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Jellyfish stings. It is unclear if topical papain is beneficial in individuals with jellyfish stings. Details: A small clinical study in individuals with jellyfish stings shows that submerging affected skin into a solution with a papain-containing meat tenderizer (Adolph's meat tenderizer), starting two minutes after a jellyfish sting and continuing for at least 20 minutes, is less effective than hot water alone in decreasing pain caused by the jellyfish sting (67835).
• Ocular floaters. Oral papain 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 symptomatic ocular floaters shows that taking 1, 2, or 3 capsules daily of an oral mixed fruit enzyme product containing papain 95 mg, ficin 95 mg, and bromelain 190 mg for 3 months leads to 55%, 63%, and 70% of floaters completely disappearing, respectively, when compared to baseline, as well as significant improvements when compared with vitamin C. Additionally, in patients with vitreous hemorrhage-induced symptomatic ocular floaters, taking 3 capsules daily of the same mixed fruit enzyme product for 3 months leads to 56% of floaters completely disappearing and improves visual acuity when compared to baseline, as well as significant improvements when compared with vitamin C (111650). It is unclear if these effects are due to papain, other ingredients, or the combination.
• Pressure ulcers. Although there has been interest in using topical papain for pressure ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Radiation dermatitis. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients receiving pelvic radiotherapy shows that taking three capsules of a specific combination product (Wobe-Mugos E, Mucos Pharma) containing papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg per capsule, four times daily, beginning 3 days prior to radiotherapy and continuing until the last day of therapy, does not attenuate skin deterioration when compared with placebo (67834). However, another small, open-label clinical study in patients with uterine carcinoma shows that taking three capsules of the same combination product four times daily, beginning 7 days before radiotherapy and continuing for 9 weeks, reduces skin reactions when compared with control (67831). It is unclear if these findings are due to papain, other ingredients, or the combination.
• Radiation-induced cystitis. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with uterine carcinoma receiving radiotherapy shows that taking three capsules of a specific combination product (Wobe-Mugos E, Mucos Pharma) containing papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg per capsule, four times daily, beginning 7 days before radiotherapy and continuing for 9 weeks, reduces genitourinary symptoms when compared with control (67831).
• Radiation-induced nausea and vomiting. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients receiving pelvic radiotherapy shows that taking three capsules of a specific combination product (Wobe-Mugos E, Mucos Pharma), containing papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg per capsule, four times daily, beginning 3 days prior to radiotherapy and continuing until the last day of therapy, does not reduce radiation-related nausea or vomiting when compared with placebo (67834).
• Tonsillopharyngitis. Oral papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Two small clinical studies in patients with pharyngitis and/or tonsillitis shows that use of throat lozenges containing papain 2 mg, lysozyme 5 mg, and bacitracin 200 IU daily for 4 days reduces pain and inflammation of the throat and lymph nodes when compared with placebo or disinfectant alone (964,968). It is unclear if these findings are due to papain, other ingredients, or the combination.
• Traumatic oral ulcers. Although there has been interest in using topical papain for traumatic oral ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Venous leg ulcers. Although there has been interest in using topical papain for venous leg ulcers, there is insufficient reliable information about the clinical effects of papain for this purpose.
• Wound healing. Topical papain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with purulent wounds shows that applying papain 1% solution plus dimethylsulfoxide (DMSO) followed by phonophoresis, a process by which ultrasound is used to increase topical drug delivery, improves wound healing when compared to baseline (67843). The validity of this finding is limited by the lack of a comparator group. Also, it is unclear if these findings are due to papain, DMSO, or the combination. More evidence is needed to rate papain for these uses.

(Read more about PAPAIN)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. It is unclear if oral sweet almond is beneficial in patients with aging skin. Details: Preliminary clinical research in postmenopausal females shows that consuming sweet almonds as 20% of daily energy intake for 16 weeks reduces wrinkle severity scores by approximately 8% when compared with consuming a calorie-matched snack (101756).
• Atopic dermatitis (eczema). Topical sweet almond oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with xerotic eczema shows that applying an emollient containing lactic acid 5% and refined sweet almond oil 10%, with or without polidocanol 5%, twice daily (Antidry Lotion or Antidry Calm) for 2 weeks reduces itching by up to 69% when compared with baseline. Benefits occurred within 30 minutes of the first use and seemed to be related to improved moisture and lipid content of the skin (101788).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral sweet almond extract is beneficial in patients with ADHD. Details: Preliminary clinical research in children aged 6-14 years old with ADHD shows that taking sweet almond extract syrup, 5 mL three times daily, for 8 weeks does not affect parent- or teacher-rated hyperactivity or inattention scores when compared with methylphenidate 1 mg/kg orally daily. This study may have been inadequately powered to detect a difference between groups (101783).
• Cancer. Although there has been interest in using oral sweet almond for cancer, there is insufficient reliable information about the clinical effects of sweet almond for this purpose.
• Cardiovascular disease (CVD). Although there has been interest in using oral sweet almond for CVD, there is insufficient reliable information about the clinical effects of sweet almond for this purpose.
• Coronary heart disease (CHD). It is unclear if oral sweet almond is beneficial for the prevention or treatment of CHD. Details: A small clinical trial in patients with hypercholesterolemia has found that intake of sweet almonds for 4 weeks is associated with decreased CHD risk based on the Framingham 10-year risk score. Each 30-gram intake of sweet almonds was associated with an estimated 3.5% decrease in risk scores (99940). In 2003, the US Food and Drug Administration (FDA) determined that it would allow a qualified health claim stating that consuming 1.5 ounces of almonds per day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of CHD. However, the FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102331). It is unclear if sweet almonds improve outcomes in patients with CHD. Preliminary clinical research in adults with CHD shows that incorporating sweet almonds 85 grams daily into a National Cholesterol Education Program (NCEP) Step I diet for 6 weeks does not improve total or low-density lipoprotein (LDL) cholesterol, blood pressure, vascular function, or inflammatory markers when compared to the NCEP Step 1 diet without sweet almonds (99938). However, the short duration of this study limits the validity of the findings.
• Constipation. It is unclear if oral or topical sweet almond is beneficial in patients with constipation. Details: A small single-blinded clinical study in older adults with constipation shows that taking sweet almond oil 9 mL twice daily or abdominal massage with 18 mL of sweet almond oil every other day for 2 weeks both independently improve symptoms of constipation, stool consistency, and quality of life when compared with no treatment. Improvement in constipation and quality of life were also superior with oral sweet almond oil over sweet almond oil massage (111392). The validity of these findings is limited by a lack of placebo control.
• Diabetes. It is unclear if oral sweet almond is beneficial in patients with diabetes. Details: Research on whether sweet almond improves glycemic control in patients with diabetes is conflicting. A small study in patients with type 2 diabetes and mild hyperlipidemia shows that consuming sweet almonds as 20% of energy intake (approximately 60 grams daily) as part of a National Cholesterol Education Program (NCEP) Step II diet for 4 weeks, along with hypoglycemic medications, improves measures of glycemic control, as well as lipids and adiposity. Fasting insulin and glucose levels decreased by 4% and 1%, respectively, when compared with the diet without sweet almonds. Also, low-density lipoprotein (LDL) cholesterol levels were reduced by about 12% (99941). Preliminary clinical research also shows that regularly consuming sweet almonds as part of a low-carbohydrate diet for 12 weeks is more effective than consuming cheese, but no more effective than peanuts, for reducing glycated hemoglobin (HbA1c) levels (99943,101787). However, the change in HbA1c demonstrated in these small trials may not be considered clinically relevant. In contrast, meta-analyses of many clinical trials in patients with a variety of metabolic disorders, including diabetes, shows that eating almonds 5-85 grams daily, or as 10% to 20% of energy, for 4-24 weeks does not improve fasting blood glucose levels, HbA1c, insulin levels, or measures of insulin resistance when compared with control (109019,111395).
• Hyperlipidemia. Small clinical studies suggest that oral sweet almond might reduce total cholesterol and low-density lipoprotein (LDL) cholesterol in patients with hyperlipidemia, but it does not appear to improve other lipid levels in these patients. Details: Several small clinical studies in adults with hyperlipidemia show that consuming raw sweet almonds 42.5-100 grams or taking sweet almond oil 10 mL daily for 4-9 weeks reduces low-density lipoprotein (LDL) cholesterol levels by 3% to 15% when compared with control diets or baseline levels. Most of these studies failed to show improvements in high-density lipoprotein (HDL) cholesterol levels or triglyceride levels when compared with control (76725,76737,99939,101786), although one study showed a 4% improvement in HDL levels (99940). A meta-analysis of 8 clinical trials in patients with hyperlipidemia or in which at least half of the patients were classified as having hyperlipidemia shows that consuming sweet almonds or taking sweet almond oil daily for 4-12 weeks modestly reduces total cholesterol and LDL cholesterol but does not improve very low-density lipoprotein (VLDL) cholesterol, triglycerides, or HDL cholesterol when compared with placebo or no treatment (111395).
• Hypertension. It is unclear if oral sweet almond is beneficial in patients with hypertension. Details: A meta-analysis of 10 small clinical studies in which at least half of the patients in each study were classified as having hypertension at baseline shows that taking sweet almond does not improve systolic or diastolic blood pressure when compared with placebo or no treatment (111395). The validity of these findings is limited by a high degree of heterogeneity across the studies.
• Insomnia. It is unclear if oral sweet almond is beneficial in patients with insomnia. Details: Preliminary clinical research in students shows that consuming ten sweet almonds daily for 2 weeks reduces the percentage of students reporting insomnia on sleep surveys from 78% to 69% (101784). The validity of this study is limited by the lack of a control group.
• Impaired glucose tolerance (prediabetes). It is unclear if oral sweet almond is beneficial in patients with prediabetes. Details: A small clinical study in adults with prediabetes shows that consuming 20 grams of sweet almonds 30 minutes before breakfast, lunch, and dinner daily for 3 months reduces fasting blood glucose and glycated hemoglobin (HbA1c) by 6 mg/dL and 0.4%, respectively, and improves measures of insulin resistance when compared with a control group. For every 4 patients consuming sweet almonds, one additional patient experienced normalization of HbA1c. Body weight, body mass index (BMI), total cholesterol, and low-density lipoprotein (LDL) cholesterol were also improved with sweet almond over control (111389).
• Irritable bowel syndrome (IBS). It is unclear if oral sweet almond flour is beneficial in patients with IBS. Details: Preliminary clinical research in patients with diarrhea-predominant IBS shows that taking sweet almond flour 40 grams orally daily for 20 days does not improve IBS symptom scores when compared with a wheat flour placebo. In fact, those taking sweet almond flour experienced an increase in severity of pain and the number of bowel movements (101785).
• Obesity. It is unclear if oral sweet almond is beneficial in patients with obesity. Details: A moderate-sized clinical study in adults with overweight and obesity shows that consuming 30-50 grams of sweet almonds does not reduce self-reported appetite ratings or subsequent short-term energy intake despite favorable changes in appetite-regulating hormones when compared with a carbohydrate-rich snack as a control (111388). Other preliminary clinical research in adults with overweight or obesity shows that following a calorie-restricted diet with almonds as 15% of total daily energy for 12 weeks increases fat loss by 2.4-fold, but does not affect total weight loss, when compared with a nut-free, calorie-restricted diet (99937). Another preliminary clinical study in mainly overweight individuals shows that consuming sweet almonds 56 grams daily for 4 weeks in addition to the regular diet reduces levels of total and low-density lipoprotein (LDL) cholesterol by approximately 5% when compared with eating isocaloric cookies. However, there was no effect on body weight, body composition, glycemic control, or blood pressure (101790).
• Psoriasis. Although there has been interest in using topical sweet almond oil for psoriasis, there is insufficient reliable information about the clinical effects of sweet almond for this purpose.
• Radiation dermatitis. It is unclear if topical sweet almond ointment is beneficial in patients with radiation dermatitis. Details: Preliminary clinical research in females receiving radiation therapy for breast cancer shows that topical use of a sweet almond ointment once before each treatment and once a few hours after each treatment does not prevent radiation dermatitis when compared with chamomile extract cream (76740).
• Stretch marks (striae gravidarum). It is unclear if topical sweet almond oil is beneficial in patients with stretch marks. Details: Preliminary clinical research in nulliparous patients shows that topical application of sweet almond oil twice daily, starting at gestational week 16 and continued until delivery, does not reduce the size or number of stretch marks when compared with control. However, using the sweet almond oil modestly reduced itching scores (97322). More evidence is needed to rate sweet almond for these uses.

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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 (18275,91113,103297,108148,108149,113899). Additionally, a retrospective cohort study in critically ill patients with severe burns suggests that use of bromelain as a debriding agent for up to 4 hours is not associated with a greater risk of bacteremia (113899).

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

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LIKELY SAFE ...when the fresh or dried fruit is used orally in amounts commonly found in foods.

POSSIBLY SAFE ...when fig fruit paste is consumed orally in amounts of up to 300 grams daily for up to 8 weeks (99956).

POSSIBLY UNSAFE ...when fig leaf decoctions are used topically. Fig leaf contains psoralens (12579,12581). There have been reports of photodermatitis with burn-like lesions and rashes after fig decoctions were applied prior to sun exposure (49962,49968,49973,49975,49981). There is insufficient reliable information available about the safety of fig leaf when used orally.

PREGNANCY AND LACTATION: LIKELY SAFE
when the fresh or dried fruit is used orally in amounts commonly found in foods. There is insufficient reliable information available about the safety of fig leaf or fruit used in medicinal amounts during pregnancy and lactation; avoid use.

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

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

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

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

POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes, short-term. Papain has been used in combination with other proteolytic enzymes at a dose of up to 1200 mg daily for up to 9 weeks (964,965,968,67831,67834). ...when used topically as a diluted solution in appropriate doses for up to 20 minutes (67835,67843,67845).

POSSIBLY UNSAFE ...when used orally in large amounts. In excessive doses, papain can cause significant side effects including esophageal perforation (6). ...when raw papain is used topically. Raw papain or papaya latex is a severe irritant and vesicant (6).

PREGNANCY: POSSIBLY UNSAFE
when used orally. There is some concern that crude papain is teratogenic and embryotoxic (6).

LACTATION:
Insufficient reliable information available; avoid using.

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LIKELY SAFE ...when used in amounts commonly found in foods. Sweet almond is commonly eaten as a food (99937,99938,99939,99941). There is insufficient reliable information available about the safety of sweet almond when used orally or topically in medicinal amounts.

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

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

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

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, fig leaf might enhance the blood glucose lowering effects of hypoglycemic drugs.  Details A small clinical study in patients with type 1 diabetes shows that consuming a tea made from fig leaves modestly reduces postprandial glucose levels and insulin requirements (12578).

INSULIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Fig leaf may enhance the blood glucose lowering effects of insulin.  Details A small clinical study in patients with type 1 diabetes shows that consuming a tea made from fig leaves modestly reduces postprandial glucose levels and insulin requirements (12578).

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WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, papain might increase the effects and side effects of warfarin.  Details In one case report, a patient previously stable on warfarin was found to have an international normalization ratio (INR) of 7.4, which was attributed to ingestion of a supplement containing papain from papaya extract (613).

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

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

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

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

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General ...Orally, the fresh or dried fig fruit is well tolerated in amounts commonly found in foods. A thorough evaluation of safety outcomes has not been conducted when fig fruit is used orally as medicine.
Topically, fig leaf may cause photodermatitis. There is limited reliable information available about the safety of fig fruit or latex when applied topically.
Serious Adverse Effects (Rare):
Orally: Allergy and, in rare cases, anaphylaxis.
Topically: The fig leaf may cause photodermatitis.

Dermatologic ...Topically, fig leaf might cause photodermatitis. The leaf contains psoralens (12579,12581). Many cases of photodermatitis from fig leaf have been reported (49962,49968,49973,49975,49981). In at least two cases, the burns were serious enough to require hospitalization. Severe anemia and sepsis developed in one patient (49962). Avoid excessive sunlight or ultraviolet light exposure while using products containing fig leaf.

Orally, fig fruit is unlikely to cause photodermatitis (12581).

Immunologic ...Orally, fig fruit can cause allergy and, in rare cases, anaphylaxis (8815,12580). Topically, exposure to fig fruit and leaves can cause contact dermatitis. In some cases, sun exposure can make contact dermatitis worse (12689,99961).

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

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

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General ...Orally and topically, papain seems to be well tolerated when used short-term at appropriate doses. Taking high oral doses may be unsafe.
Most Common Adverse Effects:
Orally: Allergic reactions in sensitive individuals.
Topically: Urticaria and pruritus in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Esophageal perforation and severe gastritis with high doses.

Dermatologic ...Topically, papain can cause itching (966). Urticarial reactions and itching have been reported in people occupationally exposed to papain, with papain confirmed as the causative agent by skin prick tests or radioallergosorbent tests (RAST) (95533,95534). In a randomized controlled trial assessing the effects of papain, trypsin, and chymotrypsin on adverse effects from radiotherapy, moderate to severe epitheliolysis was more frequent in the enzyme-treated group than the placebo group (67834). It is unclear if this adverse effect is due to papain, other enzymes, or the combination.

Gastrointestinal ...Orally, papain has been associated with diarrhea. In a randomized controlled trial assessing the effects of papain, trypsin, and chymotrypsin on adverse effects from radiotherapy, moderate to severe diarrhea was more frequent in the enzyme-treated group than the placebo group (67834). However, it is unclear if this adverse effect is due to papain, other enzymes, or the combination. Papain has also been associated with gastric ulcers and esophageal perforation in case reports of phytobezoars treated with papain (67848). In general, large amounts of papain can cause esophageal perforation (6). Ingestion of papaya latex (raw papain) can cause severe gastritis.

Genitourinary ...Orally, papain has been associated with hypernatremia in case reports of phytobezoars treated with papain (67848).

Immunologic ...Orally, papain may cause allergic reactions, including itchy watery eyes, runny nose, sneezing, abdominal cramps, sweating, and diarrhea, in individuals sensitive to papain (6,967). Occupational exposure to airborne papain dust may also cause respiratory allergic reactions (95532,95533,95534,95535,95536).

Pulmonary/Respiratory ...Occupational exposure to airborne papain dust may cause respiratory allergic reactions. Symptoms include rhinitis, sneezing, conjunctivitis, dyspnea, wheezing, cough, and asthma. In most cases, papain is confirmed as the causative agent by skin prick tests, radioallergosorbent tests (RAST), or detection of papain-specific immunoglobulin E (IgE) and IgG (95532,95533,95534,95535,95536).

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General ...Orally, when consumed as food, sweet almond is well tolerated. Orally and topically, when used as medicine, adverse effects from sweet almond seem to be rare; however, a thorough safety evaluation has not been conducted.
Most Common Adverse Effects:
Orally: Allergic reactions.
Topically: Dermatitis, itching.

Dermatologic ...Topically, itching, dermatitis, and worsening eczema have been reported in a clinical trial (101788).

Immunologic ...Tree nuts, which include almonds, can cause allergic reactions in sensitive individuals. Due to the prevalence of this allergy in the general population, tree nuts are classified as a major food allergen in the United States (105410).

Neurologic/CNS ...Orally, adverse effects to sweet almond extract in syrup have included increased sleep (101783).

Other ...Orally, adverse effects to sweet almond extract in syrup have included increased appetite (101783).

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