FYI Restore by Garden of Life

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.

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POSSIBLY EFFECTIVE

• Hypercholesterolemia. Oral Ecklonia cava seems to reduce levels of low-density lipoprotein (LDL) cholesterol. Details: Clinical research in patients with hypercholesterolemia shows that taking Ecklonia cava polyphenols (Botamedi Inc.) 200 mg twice daily for 12 weeks reduces LDL cholesterol by 11% when compared with taking placebo (106336). Also, preliminary clinical research in patients with hypercholesterolemia shows that taking a different Ecklonia cava polyphenol extract (Seapolynol, Livechem, Inc.) 400 mg once daily for 12 weeks reduces levels of LDL cholesterol by 9% when compared with baseline (106335). In overweight adults, many with hypercholesterolemia, clinical research shows that taking Ecklonia cava polyphenols 72 mg or 144 mg daily for 12 weeks reduces LDL cholesterol levels by 10% and 14%, respectively, when compared with placebo (96376). Taking Ecklonia cava does not seem to increase levels of high-density lipoprotein (HDL) cholesterol or reduce levels of triglycerides (96376,106335,106336).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Asthma. Although there is interest in using oral Ecklonia cava for asthma, there is insufficient reliable information about the clinical effects of Ecklonia cava for this condition.
• Athletic performance. It is unclear if oral Ecklonia cava is beneficial for improving athletic performance. Details: Preliminary clinical research in male college students shows that taking Ecklonia cava polyphenols 72 mg as part of 180 mL of a sport drink 30 minutes before exercise increases the time to exhaustion by approximately 2.4 minutes when compared with the sport drink alone (96377).
• Cancer. Although there is interest in using oral Ecklonia cava for cancer, there is insufficient reliable information about the clinical effects of Ecklonia cava for this condition.
• Cardiovascular disease (CVD). Although there is interest in using oral Ecklonia cava for CVD, there is insufficient reliable information about the clinical effects of Ecklonia cava for this condition.
• Diabetes. Although there is interest in using oral Ecklonia cava for diabetes, there is insufficient reliable information about the clinical effects of Ecklonia cava for this condition.
• Erectile dysfunction (ED). Although there is interest in using oral Ecklonia cava for ED, there is insufficient reliable information about the clinical effects of Ecklonia cava for this condition.
• Fatigue. Although there is interest in using oral Ecklonia cava for various causes of fatigue, there is insufficient reliable information about the clinical effects of Ecklonia cava for this use.
• Fibromyalgia. Although there is interest in using oral Ecklonia cava for fibromyalgia, there is insufficient reliable information about the clinical effects of Ecklonia cava for this use.
• Impaired glucose tolerance (prediabetes). It is unclear if oral Ecklonia cava is beneficial for prediabetes. Details: Preliminary clinical research in adults with prediabetes shows that taking a specific Ecklonia cava extract (AG-dieckol, Aqua Green Tech Co.) 500 mg three times daily for 12 weeks reduces postprandial glucose levels by 5.5%, compared with a small increase in those taking placebo. However, Ecklonia cava extract did not improve fasting blood glucose, insulin sensitivity, or glycated hemoglobin (HbA1c) when compared with placebo (96375).
• Insomnia. Although there is interest in using oral Ecklonia cava for insomnia, there is insufficient reliable information about the clinical effects of Ecklonia cava for this use.
• Male infertility. Although there is interest in using oral Ecklonia cava for male infertility, there is insufficient reliable information about the clinical effects of Ecklonia cava for this condition.
• Metabolic syndrome. Although there is interest in using oral Ecklonia cava for metabolic syndrome, there is insufficient reliable information about the clinical effects of Ecklonia cava for this condition.
• Neuropathic pain. Although there is interest in using oral Ecklonia cava for neuropathic pain, there is insufficient reliable information about the clinical effects of Ecklonia cava for this condition.
• Obesity. It is unclear if oral Ecklonia cava polyphenols improve weight loss or body composition; the available research is conflicting. Details: A small clinical trial in individuals with a body mass index (BMI) between 25 kg/m2 and 30 kg/m2 shows that taking Ecklonia cava polyphenols (Seapolynol, Botamedi Inc.) 180 mg twice daily for 12 weeks does not reduce body weight, BMI, body fat percentage, or low-density lipoprotein (LDL) cholesterol levels when compared with placebo. However, in a sub-group of patients with abdominal obesity, Ecklonia cava modestly reduced total adipose tissue levels and fat mass and increased skeletal muscle mass when compared with placebo. All patients in this study increased physical activity and consumed a diet with a mild caloric restriction (106334). Conversely, other clinical research in a similar population shows that taking Ecklonia cava polyphenols 144 mg daily for 12 weeks reduces body fat ratio by 7% and body weight, BMI, and waist circumference by 2%. These improvements were statistically significant when compared with placebo. Furthermore, taking Ecklonia cava polyphenols 72 mg or 144 mg daily reduces LDL cholesterol levels by 10% and 14%, respectively, when compared with placebo (96376). The reasons for these discrepant findings are unclear.
• Osteoarthritis. Although there is interest in using oral Ecklonia cava for osteoarthritis, there is insufficient reliable information about the clinical effects of Ecklonia cava for this condition.
• Radiation exposure. Although there is interest in using oral Ecklonia cava for radiation exposure due to its iodine content, there is insufficient reliable information about the clinical effects of Ecklonia cava for this use. More evidence is needed to rate Ecklonia cava for these uses.

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POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angina. Although there has been interest in using oral nattokinase for angina, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Atherosclerosis. It is unclear if nattokinase is beneficial in patients with atherosclerosis. Details: Clinical research in patients at low risk for cardiovascular disease shows that taking nattokinase 2000 fibrinolytic units orally daily for a median of 3 years is not associated with any change in subclinical atherosclerosis, as measured by carotid artery intima-media thickness and carotid arterial stiffness, when compared with placebo (106406). However, a retrospective observational study of Chinese patients with hyperlipidemia and/or mild atherosclerosis has found that taking nattokinase 10,800 fibrinolytic units daily for 12 months may modulate the progression of atherosclerosis. Nattokinase use was associated with a 22% reduction in carotid artery intima-media thickness and a 36% reduction in the size of the carotid artery plaque when compared to baseline. These effects appear to be enhanced by regular exercise, avoidance of smoking and alcohol, and co-administration with aspirin (111252). The validity of these findings is limited by a lack of control group and the retrospective nature of the study.
• Cancer. Although there has been interest in using oral nattokinase for cancer, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Cardiovascular disease (CVD). Although there has been interest in using oral nattokinase for CVD, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral nattokinase for CFS, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Endometriosis. Although there has been interest in using oral nattokinase for endometriosis, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Fibromyalgia. Although there has been interest in using oral nattokinase for fibromyalgia, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Hemorrhoids. Although there has been interest in using oral nattokinase for hemorrhoids, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Hyperlipidemia. It is unclear if oral nattokinase is beneficial in patients with hyperlipidemia. Details: A retrospective observational study in Chinese patients with hyperlipidemia and/or mild atherosclerosis shows that taking nattokinase 10,800 fibrinolytic units daily for 12 months is associated with a 15% to 17% improvement in total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides when compared to baseline. This effect seems to be amplified in subjects who have a higher body mass index, smoke, drink alcohol, and exercise regularly. Furthermore, the anti-hyperlipidemic effect of nattokinase appears to be enhanced by co-administration of vitamin K2 and aspirin (111252). However, the validity of these findings is limited by a lack of control group and the retrospective nature of the study. In contrast, some preliminary clinical research in patients with hyperlipidemia shows that taking nattokinase 200 mg (7000 fibrinolytic units) daily in combination with red yeast rice 1200 mg daily in divided doses for 6 months reduces LDL cholesterol and total cholesterol when compared with placebo. However, taking nattokinase alone did not improve lipid levels when compared with placebo (92312). It is likely that the lipid lowering effects of the combination are due to red yeast rice, which contains monacolin K, a chemical similar to lovastatin.
• Hypertension. It is unclear if oral nattokinase is beneficial in patients with hypertension. Details: Some clinical research suggests that nattokinase can reduce systolic blood pressure (SBP) and diastolic blood pressure (DBP). One study in patients with hypertension shows that taking nattokinase (NSK II, Japan Bio Sciences Laboratories Company Ltd.) 2000 fibrinolytic units daily for 8 weeks reduces SBP by 6 mmHg and DBP by 3 mmHg when compared with placebo (64835). In another study, taking a natto extract 30 grams daily (unknown nattokinase content) for 4 days reduces SBP and DBP by 11% and 10%, respectively, when compared with baseline (64837). However, in patients with normal blood pressure or controlled hypertension, taking nattokinase 2000 fibrinolytic units daily for a median of 3 years has no effect on blood pressure (106406).
• Impaired glucose tolerance (prediabetes). Oral nattokinase has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with prediabetes shows that taking a combination product containing nattokinase 34 fibrinolytic units, chokeberry 1.64 grams, Panax ginseng 1.36 grams, and shiitake mushroom 960 mg twice daily for 12 weeks improves measures of insulin resistance, but does not reduce fasting blood glucose, postprandial glucose, or glycated hemoglobin (HbA1c), when compared with placebo (108301).
• Infertility. Although there has been interest in using oral nattokinase for infertility, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Peripheral arterial disease (PAD). Although there has been interest in using oral nattokinase for PAD, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Stroke. Although there has been interest in using oral nattokinase for stroke, there is insufficient reliable information about the clinical effects of nattokinase for this condition.
• Venous insufficiency. It is unclear if oral nattokinase is beneficial in patients with venous insufficiency. Details: A small, uncontrolled clinical study in patients with venous insufficiency who underwent vascular surgery suggests that taking nattokinase 2000 fibrinolytic units daily for 30 days after surgery may induce remission of clinical symptoms (109553). The validity of these findings is limited by a lack of control group.
• Venous thromboembolism (VTE). It is unclear if oral nattokinase is beneficial in patients with VTE. Details: A small, uncontrolled clinical study in patients with deep vein thrombosis (DVT) or phlebitis suggests that taking nattokinase 2000 fibrinolytic units daily for 30 days after a 30-day regimen of fondaparinux or enoxaparin may induce remission of clinical symptoms (109553). The validity of these findings is limited by a lack of control group and the use of anticoagulants before nattokinase therapy. Nattokinase has also been evaluated in combination with other ingredients for prophylaxis of DVT during long-haul flights. A small clinical trial shows that taking two capsules of a specific combination product (Flite Tabs, Aidan), containing 150 mg of a proprietary blend of nattokinase and maritime pine bark (Pycnogenol, Horphag Research), 2 hours before a flight and 6 hours later, might decrease the risk of DVT during long plane flights (12075). The effect of nattokinase alone on DVT risk during long-haul flights is unclear. More evidence is needed to rate nattokinase for these uses.

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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).
• 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)

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))

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bronchiectasis. A small clinical study in patients with bronchiectasis shows that taking serrapeptase 30 mg daily for 4 weeks significantly reduces frequency of cough and also seems to decrease sputum viscosity and neutrophil counts in sputum samples when compared with no treatment (13153).
• Chronic bronchitis. A small clinical study in patients with chronic bronchitis shows that taking serrapeptase 30 mg daily for 4 weeks significantly reduces frequency of cough and expectoration and also seems to decrease sputum viscosity and neutrophil counts in sputum samples when compared with no treatment (13153).
• Laryngitis. A clinical study in patients with acute or chronic ear, nose, or throat disorders, including laryngitis, shows that taking serrapeptase 10 mg three times daily reduces pain, secretions, difficulty swallowing, and body temperature after 3-4 days of treatment when compared with placebo (13152).
• Pharyngitis. A clinical study in patients with acute or chronic ear, nose, or throat disorders, including pharyngitis, shows that taking serrapeptase 10 mg three times daily reduces pain, secretions, difficulty swallowing, and body temperature after 3-4 days of treatment when compared with placebo (13152).
• Postoperative swelling. Serrapeptase has been evaluated for reducing facial swelling after a variety of procedures. A clinical study in patients undergoing maxillary antrostomy for empyema shows that taking serrapeptase 10 mg orally three times on the day before surgery, once in the evening after surgery, and three times daily for 5 days after surgery modestly reduces buccal swelling when compared with placebo (13151). In patients requiring removal of impacted mandibular third molars, a small clinical study in healthy adults suggests that taking serrapeptase 10 mg three times daily for 5 days improves postoperative trismus and swelling by the fourth postoperative day when compared with placebo; however, no difference in pain scores was observed (106013). The validity of these findings in limited by a lack of consistent comparison to baseline in both groups. Conversely, two other small studies in patients requiring removal of impacted mandibular third molars suggest that serrapeptase is less effective than dexamethasone or another proteolytic enzyme, consisting of trypsin, bromelain, and the flavonoid rutin, for improving swelling or facilitating wound healing (106011,106012). The validity of these findings is limited due to poor study methodologies.
• Rhinosinusitis. A clinical study in patients with acute or chronic ear, nose, or throat disorders, including rhinosinusitis, shows that taking serrapeptase 10 mg three times daily reduces pain, nasal secretions, nasal obstruction, and anosmia after 3-4 days of treatment when compared with placebo (13152). More evidence is needed to rate serrapeptase for these uses.

(Read more about SERRAPEPTASE)

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 a specific Ecklonia cava phlorotannin extract (SeaPolynol) is used orally and appropriately. Doses of up to 400 mg daily have been used with apparent safety for 12 weeks (106334,106336). According to the European Food Safety Authority (EFSA), doses of up to 263 mg daily are considered safe based on extrapolation from animal toxicity research (106333). ...when other sources of Ecklonia cava polyphenols are used orally, short-term. Doses up to 144 mg daily have been used with apparent safety for up to 12 weeks (96376). ...when a specific Ecklonia cava polyphenol-rich extract (AG-dieckol, Aqua Green Tech Co.) is used orally and appropriately. Doses of up to 1500 mg daily have been used with apparent safety for up to 12 weeks (96375).

CHILDREN: POSSIBLY SAFE
when a specific Ecklonia cava phlorotannin extract (SeaPolynol) is used orally and appropriately in children 12 years and older. According to the EFSA, doses of up to 163 mg daily are considered safe in children aged 12-14 years, and 230 mg daily is considered safe in children aged 14 years and above, based on extrapolation from animal toxicity research (106333). There is insufficient reliable information available about the safety of Ecklonia cava in children under 12 years of age.

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

(Read more about ECKLONIA CAVA)

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

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

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

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

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

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

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

(Read more about LAMINARIA)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Nattokinase is a natural component of the soy food natto. It has been routinely consumed in Japan for hundreds of years (12072,12073).

POSSIBLY SAFE ...when used orally for medicinal purposes. Nattokinase has been used with apparent safety in doses of 2000 fibrinolytic units daily for up to 3 years or 10,800 fibrinolytic units daily for up to 12 months (64835,92312,106406,111252).

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

(Read more about NATTOKINASE)

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.

(Read more about PAPAIN)

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))

POSSIBLY SAFE ...when used orally and appropriately, short-term. Serrapeptase seems to be safe when used in clinical trials lasting up to 4 weeks (13151,13152,13153). There is insufficient reliable information available about the safety of serrapeptase when used long-term.

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

(Read more about SERRAPEPTASE)

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 ECKLONIA CAVA)

ACE INHIBITORS (ACEIs) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, laminaria might increase the risk of hyperkalemia when taken with ACEIs.  Details Laminaria contains potassium (19).

AMIODARONE (Cordarone) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining laminaria with amiodarone might cause excessively high iodine levels.  Details Amiodarone contains 37.3% iodine and can increase iodine levels. Concomitant use with laminaria supplements, some of which may contain as much as 1000 mcg iodine, might increase the risk of adverse effects from iodine, including altered thyroid function (9556,94046).

ANTITHYROID DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Due to its iodine content, laminaria might alter the effects of antithyroid drugs.  Details Some laminaria supplements contain up to 1000 mcg of iodine (9556,94046). Iodine in high doses has been reported to cause both hyperthyroidism and hypothyroidism, depending on the individual's past medical history. Taking laminaria could theoretically alter the effects of antithyroid drugs.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, laminaria might increase the risk of hyperkalemia, which could increase the effects and adverse effects of digoxin.  Details Laminaria contains potassium (19).

POTASSIUM-SPARING DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, laminaria might increase the risk of hyperkalemia when taken with potassium-sparing diuretics.  Details Laminaria contains potassium (19).

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Due to its iodine content, laminaria might alter the effects of thyroid hormone.  Details Some laminaria supplements contain up to 1000 mcg of iodine (9556,94046). Iodine in high doses has been reported to cause both hyperthyroidism and hypothyroidism, depending on the individual's past medical history. Taking laminaria could theoretically alter the effects of thyroid hormone.

(Read more about LAMINARIA)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Nattokinase might increase the risk of bleeding when used with anticoagulant/antiplatelet drugs.  Details Nattokinase has thrombolytic and anticoagulant effects (12070,12073,92311). There is a case report of intracranial hemorrhage in a patient who added nattokinase to aspirin therapy (64834).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, nattokinase might increase the risk of hypotension when used with antihypertensive drugs.  Details Some clinical research suggests that nattokinase may reduce systolic and diastolic blood pressure (64835,64837).

(Read more about NATTOKINASE)

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).

(Read more about PAPAIN)

(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

(Read more about SERRAPEPTASE)

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, Ecklonia cava extract and Ecklonia cava polyphenols seem to be well tolerated.

Dermatologic ...Orally, alopecia has been reported by one person in a clinical trial (106335).

Gastrointestinal ...Orally, nausea, dyspepsia, and diarrhea have been reported by one person each in a clinical trial (106335).

(Read more about ECKLONIA CAVA)

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

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

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

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

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

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

(Read more about LAMINARIA)

General ...Orally, nattokinase is generally well tolerated. Preliminary clinical trials suggest that the incidence of adverse effects with nattokinase is similar to that with placebo.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis, hemorrhage.

Hematologic ...Orally, nattokinase has been associated with rare reports of hemorrhage (64834,109551). A case of intracranial hemorrhage (ICH) has been reported in a 52-year-old female who took nattokinase while taking low-dose aspirin for secondary prevention of ischemic stroke. Seven days after initiating nattokinase 400 mg daily, the patient reported vertigo and unsteady gait and was diagnosed with an acute cerebellar hemorrhage. It was suggested that the thrombolytic and anticoagulant effects of nattokinase combined with aspirin's antiplatelet effects contributed to the ICH (64834). In another case, a 92-year-old female taking nattokinase daily (dose unknown) for atrial fibrillation presented to the hospital after a fall. The patient was on no other anticoagulant or antiplatelet drugs. Abdominal CT showed a ruptured hepatic cystic lesion and intraperitoneal hemorrhage, which was difficult to stop despite several transfusions of red blood cells and fresh frozen plasma. The authors attributed the bleeding complications, in part, to nattokinase use (109551).

Immunologic ...Orally, nattokinase can cause hypersensitivity reactions, including anaphylaxis, in individuals sensitive to natto (109552,111253). A case series examining hypersensitivity reactions to natto shows that the causative allergen can be either nattokinase or polygamma glutamic acid (PGA), both of which are found in the sticky substance surrounding natto soybeans. In patients with hypersensitivity to nattokinase, specifically, symptoms occurred within 2 hours after ingestion, were limited to the pharynx and larynx, and included swelling, tightness, and itching in the throat and lips and dyspnea. All patients with nattokinase sensitivity shared a history of atopic dermatitis (111253).

(Read more about NATTOKINASE)

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).

(Read more about PAPAIN)

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))

General ...Orally, serrapeptase seems to be well-tolerated. Some patients have reported epigastric pain, gastrointestinal upset, and nausea; however, these side effects appear to occur at the same rate as placebo (13152).

Gastrointestinal ...Orally, some patients have reported experiencing epigastric pain, gastrointestinal upset, and nausea; however, these side effects appear to occur at the same rate as placebo (13152).

Immunologic ...There is a case report of bullous pemphigoid, an autoimmune subepidermal dermatosis, in an elderly man who took serrapeptase (13154).

(Read more about SERRAPEPTASE)