Apple Cider Vinegar with Bromelain and Apple Pectin 600 mg by TerraVita Premium Collection

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there has been interest in using topical apple cider vinegar for acne, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Athletic performance. It is unclear if oral apple cider vinegar is beneficial for improving endurance during exercise. Details: Preliminary clinical research in a small number of healthy male athletes shows that drinking apple cider vinegar 500 mL one-hour prior to an endurance cycling test does not improve endurance capacity, as measured by respiratory exchange rate, heart rate, or blood levels of ammonia, glucose, or lactate, when compared with a commercial sports drink (103225). It is unknown if apple cider vinegar would improve endurance when compared with a placebo control.
• Atopic dermatitis (eczema). Although there has been interest in using topical apple cider vinegar for eczema, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Cognitive function. Although there has been interest in using oral apple cider vinegar to improve cognitive function, there is insufficient reliable information about the clinical effects of apple cider vinegar for this use.
• Coronavirus disease 2019 (COVID-19). Although there has been interest in using oral apple cider vinegar for COVID-19, there is insufficient reliable information about the clinical effects of apple cider vinegar for this use.
• Dandruff. Although there has been interest in using topical apple cider vinegar for dandruff, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Dental plaque. It is unclear if topical apple cider vinegar prevents the accumulation of dental plaque. Details: A small clinical study in children aged 3-6 years with cerebral palsy shows that applying apple cider vinegar 5% to their teeth daily for 6 months reduces the accumulation of dental plaque when compared with manual tooth brushing without dental paste (111228). However, the validity of these findings is limited by a lack of blinding and poor study methodology.
• Depression. Although there has been interest in using oral apple cider vinegar for depression, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Diabetes. It is unclear if oral apple cider vinegar is beneficial for improving glucose control in patients with type 2 diabetes; evidence is conflicting. Details: Two meta-analyses of mainly lower-quality clinical trials in a variety of populations (i.e., healthy, overweight, or obese individuals or those with type 2 diabetes) show that taking apple cider vinegar daily for up to 12 weeks reduces fasting blood glucose (FBG) levels by about 8-21 mg/dL, glycated hemoglobin (HbA1c) by 0.5%-0.9%, and total cholesterol by 6-7 mg/dL when compared with control (e.g., water, another beverage, no beverage, or restricted calorie diet). There was no effect on levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, insulin, or on measures of insulin resistance. However, in sub-group analyses limited to patients with type 2 diabetes, the effect of apple cider vinegar on FBG or HbA1c levels is conflicting (106284,112355). Of note, both meta-analyses include studies with heterogeneous populations, varied dosages, and different durations that limit the interpretation of these pooled results. Small clinical studies show varying results. One small open-label clinical study conducted in Iran in adults with type 2 diabetes shows that taking apple cider vinegar 30 mL daily for 8 weeks reduces HbA1c by about 1.4% but does not impact fasting blood glucose when compared with control (113626). Notably, baseline HbA1c was about 9% in the apple cider vinegar group versus about 8% in the control group. It is unclear if modifications to antidiabetes medications were allowed during study enrollment. Additionally, a very small clinical study shows that taking apple cider vinegar 20 grams with a meal increases postprandial insulin sensitivity and reduces postprandial flux in insulin levels in patients with insulin resistance, but not those with type 2 diabetes, when compared with placebo (17614). Additionally, a very small clinical study shows that taking apple cider vinegar 20 grams with a meal increases postprandial insulin sensitivity and reduces postprandial flux in insulin levels in patients with insulin resistance, but not those with type 2 diabetes, when compared with placebo (17614). It is unclear if the formulation of apple cider vinegar alters its effects. One small crossover study in healthy adults found a modestly greater reduction in postprandial glucose with the use of liquid apple cider vinegar (providing 1.25 grams acetic acid) when compared with apple cider vinegar whole tablets or crushed tablets (providing 1.5 grams acetic acid) or water alone (106285). Larger studies are needed to confirm this finding.
• Dyspepsia. Although there has been interest in using oral apple cider vinegar for dyspepsia, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Gastroparesis. It is unclear if oral apple cider vinegar is beneficial for gastroparesis. Details: A very small clinical study shows that taking apple cider vinegar 30 mL daily worsens the gastric emptying rate in patients with type 1 diabetes and gastroparesis when compared with drinking water (17609).
• Gingivitis. It is unclear if topical apple cider vinegar prevents the development of gingivitis. Details: A small clinical study in children aged 3-6 years with cerebral palsy shows that applying apple cider vinegar 5% to the teeth daily for 6 months reduces gingivitis scores when compared to baseline, with results comparable to manual tooth brushing without dental paste at the end of the study period (111228). However, the validity of these findings is limited by a lack of blinding and poor methodology.
• Herpes zoster (shingles). Although there has been interest in using topical apple cider vinegar for shingles, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Hyperlipidemia. It is unclear whether oral apple cider vinegar is beneficial for hyperlipidemia. Details: A small open-label clinical study conducted in Iran in adults with type 2 diabetes shows that taking apple cider vinegar 30 mL daily for 8 weeks reduces low-density lipoprotein (LDL) cholesterol and total cholesterol but does not impact high-density lipoprotein (HDL) cholesterol or triglycerides when compared with control (113626).
• Impaired glucose tolerance (prediabetes). Although there has been interest in using oral apple cider vinegar for prediabetes, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Insect bite. Although there has been interest in using topical apple cider vinegar for insect bites, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Intestinal parasite infection. Although there has been interest in using oral apple cider vinegar for intestinal parasite infections, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Kidney stones (nephrolithiasis). It is unclear if oral apple cider vinegar reduces the risk for kidney stones. Details: Some population research suggests that the consumption of fermented vinegar can reduce the risk for kidney stones (97311). However, there is currently no clinical evidence confirming this association, or any studies specifically evaluating the use of apple cider vinegar for this purpose.
• Leg cramps. Although there has been interest in using oral apple cider vinegar for leg cramps, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Obesity. It is unclear if oral apple cider vinegar is beneficial for obesity. Details: A small clinical study in adults with overweight and obesity shows that taking apple cider vinegar 15 mL twice daily for 12 weeks along with a calorie-restricted diet helps control appetite and modestly reduces body weight, body mass index (BMI), and hip girth when compared with a restricted calorie diet alone. Taking apple cider vinegar along with dieting also appears to increase high-density lipoprotein (HDL) cholesterol levels and decrease triglyceride levels, but not low-density lipoprotein (LDL) cholesterol levels, when compared to dieting alone (97310). Additionally, a small clinical study conducted in Lebanon in adolescents and young adults with overweight and obesity shows that taking 5, 10, or 15 mL of apple cider vinegar diluted in water every morning for 12 weeks modestly reduces weight and BMI when compared with placebo, with the greatest reduction observed with the 15 mL dose. Taking apple cider vinegar also modestly reduced fasting blood glucose, triglycerides, and serum cholesterol levels when compared with placebo(115305). Another small open-label clinical study conducted in Iran in adults with type 2 diabetes shows that taking apple cider vinegar 30 mL daily for 8 weeks reduces BMI and waist circumference but does not change waist-to-hip ratio when compared with control (113626). Overall, the validity of these results is limited by study size and generalizability.
• Osteoarthritis. Although there has been interest in using oral apple cider vinegar for osteoarthritis, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Pharyngitis. Although there has been interest in using oral apple cider vinegar for pharyngitis, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Rhinosinusitis. Although there has been interest in using oral apple cider vinegar for rhinosinusitis, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Sunburn. Although there has been interest in using topical apple cider vinegar for sunburn, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Vaginal candidiasis. Although there has been interest in using topical apple cider vinegar for vaginal candidiasis, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• Warts. Although there has been interest in using topical apple cider vinegar for warts, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition. More evidence is needed to rate apple cider vinegar for these uses.

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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). Further, a meta-analysis of up to 5 lower- to moderate-quality clinical and observational studies in children and adults with deep burns shows that enzymatic debridement with a specific bromelain based proteolytic enzyme gel applied once or twice for a 4 hour period reduces eschar time by approximately 7 days and reduces the relative risk of surgical excision, and autografts by 83%, and 60%, respectively, when compared with standard of care (e.g., surgical and non-surgical procedures) (115870). The validity of these results is limited by significant heterogeneity across clinical studies, including differences in the location of burns and extent of total body surface area affected.
• 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.
• Chronic venous insufficiency. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An observational study in adults with chronic venous insufficiency using compression stockings shows that taking a specific supplement containing bromelain dry extract 50-200 mg, Baikal skullcap, and horse chestnut (Lenidase, Enfarma), dose adjusted based on severity, daily for up to 90 days, improves severity of lower extremity symptoms (e.g., inflammation, pain, varicose veins, vessel induration) when compared with the use of compression stockings alone (115869). It is unclear if these benefits are due to bromelain, 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 after some 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). In contrast, several other small clinical studies show that taking bromelain does not reduce pain after wisdom tooth extraction when compared with placebo (91107,96214,96215). These studies might not have 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). Additionally, multiple clinical studies in patients undergoing oral procedures, including crown lengthening or root canal surgery, shows that bromelain 160-1500 mg, taken in 2-4 divided doses daily for up to 6 days, reduces dental pain, swelling, and trismus similarly to taking non-steroidal anti-inflammatories (e.g., ketoprofen, diclofenac sodium, aceclofenac, and ibuprofen) (91109,91110,110546,113898,115871). Bromelain, in combination with other ingredients, has also been evaluated for reducing pain after surgery. Several clinical trials in adults undergoing a variety of surgery types, including facial trauma, hernioplasty, oral surgery, and shoulder surgery, show that taking specific combination products (Siben, Brovas, Tenosan) containing bromelain and other ingredients (e.g., freeze-dried pineapple, methylsulfonylmethane, Boswellia serrata) daily for 1 week to 3 months reduces postoperative pain (19322,114687,115304,115868). However, clinical significance is unclear. Additionally, it is unclear if the effect is due to bromelain, other ingredients, or the combination.
• 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). Additionally, a moderate-sized, open-label, clinical trial in adults undergoing facial trauma surgery shows that taking 700 mg per day of bromelain combined with sweet clover and horse chestnut (Brovas, Agave Group) postoperatively for 15 days reduces facial edema when compared with control (115304). However, clinical significance of this benefit is uncertain. Additionally, it is unclear if this effect is due to sweet clover, other ingredients, or the combination.
• 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. Most clinical research shows that oral pectin at a dose of 15 grams daily can slightly lower total cholesterol and low-density lipoprotein (LDL) cholesterol levels in patients with hypercholesterolemia. Details: While some small studies in patients with or without hypercholesterolemia suggest that pectin 1-12 grams daily for up to 12 weeks does not reduce lipid levels (2215,2217), other research in patients with hypercholesterolemia shows that taking pectin 15 grams daily for 4 weeks consistently reduces total cholesterol and LDL cholesterol by around 7% to 10% when compared with baseline or placebo (2214,2216,92473). Some forms of pectin might lower cholesterol levels better than others. Pectin with a higher molecular weight and higher degree of esterification appears to be the most effective (92473). A larger clinical study also shows that taking 20 grams of pectin and guar gum, along with small amounts of insoluble fiber, reduces total cholesterol by nearly 8% and LDL cholesterol by nearly 11%, but does not improve high-density lipoprotein (HDL) cholesterol or triglycerides, when compared with placebo (12547).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Colorectal cancer. Although there has been interest in using oral pectin for the prevention of colorectal cancer, there is insufficient reliable information about the clinical effects of pectin for this purpose.
• Diarrhea. It is unclear if oral pectin is beneficial in children with persistent diarrhea. Details: A small clinical study in children aged 5-12 months in developing nations with persistent diarrhea shows that taking pectin 4 grams/kg reduces the duration of diarrhea and vomiting, and reduces the need for oral rehydration solution and intravenous fluid, when compared with a rice-diet control (12575). Pectin has also been evaluated in combination with other ingredients. One clinical study in children aged 6 months to 6 years with acute diarrhea shows that taking a combination of apple pectin and chamomile (Diarrhoesan, Dr. Loges + Co. GmbH) for up to 5 days reduces the frequency of stools by day 3 by about 1.36-fold when compared with placebo, with improvements maintained through day 5. This combination product was given hourly up to a maximum dose of 50 mL in children 6-12 months of age, 60 mL in children 1-3 years of age, and 80 mL in children 4-6 years of age (19705). It is unclear if these findings are due to pectin, chamomile, or the combination.
• Gastroesophageal reflux disease (GERD). It is unclear if oral pectin is beneficial in children with GERD. Details: A small clinical study in children with GERD and cerebral palsy shows that adding pectin to enteral nutrition in a 1:2 ratio for 4 weeks might reduce some symptoms of GERD. The number of vomiting episodes per week was reduced by 60% and the frequency of coughing/wheezing was reduced by 76% for children given the pectin diet when compared with those given a non-pectin diet (92476).
• Impaired glucose tolerance (Prediabetes). It is unclear if oral pectin is beneficial in patients with impaired glucose tolerance. Details: A small clinical study in middle-aged patients with impaired glucose tolerance or impaired fasting glucose shows that drinking 400 mL of a beverage containing 40 grams/L of sugar beet pectin in two divided doses daily for 12 weeks does not improve fasting or postprandial plasma glucose concentrations or serum lipid levels when compared to baseline (34118).
• Irritable bowel syndrome (IBS). Although there has been interest in using oral pectin for IBS, there is insufficient reliable information about the clinical effects of pectin for this purpose.
• Mercury toxicity. It is unclear if oral pectin is beneficial in patients with mercury toxicity. Details: A small clinical study in children with mercury poisoning shows that taking pectin 2.5 grams daily for 21 days and then 5 grams daily for 39 days increases mercury excretion in the urine, decreases the duration of mercury toxicity, and improves psychological symptoms when compared to baseline (31657). The validity of these findings is limited by the lack of a comparator group.
• Niacin-induced flushing. It is unclear if oral pectin is beneficial for the prevention or management of niacin-induced flushing. Details: A small clinical study shows that taking apple pectin 2 grams 30 minutes prior to taking niacin extended-release 1000 mg reduces the duration of flushing by about 35 minutes when compared with placebo. However, apple pectin does not reduce the incidence of flushing, the time to flush, or the maximum severity of flushing (92477).
• Peptic ulcers. It is unclear if oral pectin is beneficial for the prevention of peptic ulcers. Details: A small clinical study in patients with recently healed duodenal ulcers shows that taking apple pectin 10 grams twice daily for 6 months does not reduce the recurrence of duodenal ulcers when compared with placebo (31697).
• Prostate cancer. It is unclear if oral pectin is beneficial in patients with prostate cancer. Details: Two small clinical studies in patients with prostate cancer show that taking a specific modified citrus pectin product (Pectasol, Econugenics) 4.8 grams three times daily following prostatectomy, radiation, or cryosurgery for up to one year slows disease progression and increases the time to prostate specific antigen (PSA) doubling when compared to baseline (15020,108525). The validity of these findings is limited by the lack of a comparator group.
• Radiation exposure. Although there has been interest in using oral pectin to minimize exposure to environmental radiation, there is insufficient reliable information about the clinical effects of pectin for this purpose. More evidence is needed to rate pectin for these uses.

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LIKELY SAFE ...when used orally and appropriately in food amounts.

POSSIBLY SAFE ...when used orally and appropriately, short-term for medicinal purposes. Apple cider vinegar has been safely used in short-term studies for up to 12 weeks (17609,17614,97310).

POSSIBLY UNSAFE ...when used topically. Topical application of apple cider vinegar has been reported to cause chemical burns in at least three patients. Mild skin irritation is common (91662,93074,101172). ...when used orally in large amounts, long-term. A case of hypokalemia, hyperreninemia, and osteoporosis has been reported for a patient who consumed apple cider vinegar 250 mL daily for 6 years (31730).

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

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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 used in amounts commonly found in foods. Pectin has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally in amounts greater than those typically found in food. Pectin 4.8 grams three times daily has been used for up to one year without serious adverse effects (12547,15019,15020,92481,108525).

CHILDREN: POSSIBLY SAFE
when used orally in amounts greater than those found in food, short-term. Pectin 4 grams/kg has been used daily for up to 7 days without reports of serious adverse effects (12575,19705).

PREGNANCY AND LACTATION: LIKELY SAFE
when used in amounts commonly found in foods. Pectin has Generally Recognized as Safe (GRAS) status in the US (4912).

PREGNANCY AND LACTATION: POSSIBLY SAFE
when used orally in medicinal amounts (12577).

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ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking apple cider vinegar with antidiabetes drugs might increase the risk of hypoglycemia.  Details Apple cider vinegar might reduce fasting and postprandial blood glucose levels and decrease gastric emptying in people with diabetes (17609,17614,106285,106287). However, not all research agrees (106284). Theoretically, it might have additive effects on glucose levels when used with antidiabetes drugs.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of apple cider vinegar with digoxin might increase the risk of cardiac toxicity.  Details A case of hypokalemia related to chronic use of apple cider vinegar has been reported (5911). Theoretically, overuse of apple cider vinegar could decrease potassium levels, increasing the risk of toxicity with digoxin.

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of apple cider vinegar with diuretic drugs might increase the risk of hypokalemia.  Details A case of hypokalemia related to chronic use of apple cider vinegar has been reported (5911). There is some concern that people taking apple cider vinegar along with potassium depleting diuretics might have an increased risk for hypokalemia.

INSULIN Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of apple cider vinegar with insulin might increase the risk of hypokalemia.  Details A case of hypokalemia related to chronic use of apple cider vinegar has been reported (5911). Theoretically, overuse of apple cider vinegar concomitantly with insulin might increase the risk of hypokalemia (5911).

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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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DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, pectin might reduce the absorption of digoxin, potentially decreasing its effectiveness.  Details A small clinical study shows that taking digoxin with a kaolin-pectin suspension reduces the absorption of digoxin by about 62% (2212). It is unclear if these effects are due to pectin, kaolin, or the combination.

LOVASTATIN (Mevacor) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, pectin might reduce the absorption of lovastatin, potentially decreasing its effectiveness.  Details Case reports suggest that concomitant use of pectin and lovastatin might reduce the cholesterol-lowering effect of lovastatin, possibly due to reduced intestinal absorption of lovastatin (615).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, pectin might reduce the absorption of tetracycline antibiotics, potentially decreasing their effectiveness.  Details A small clinical study shows that taking tetracycline with bismuth subsalicylate in a kaolin-pectin suspension reduces the absorption of tetracycline by about 34% (2213). It is unclear if these effects are due to pectin, kaolin, bismuth subsalicylate, or the combination.

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General ...In food amounts, apple cider vinegar is well tolerated. It seems to be well tolerated when used orally, short-term for medicinal purposes. However, in larger amounts, long-term use may be unsafe.
Topically, apple cider vinegar may be unsafe.
Serious Adverse Effects (Rare):
Orally: Hypokalemia, hyperreninemia, and osteoporosis have been reported with long-term use.
Topically: Chemical burns, skin irritation.

Dermatologic ...Topically, apple cider vinegar may cause chemical burns. There is one published report of an individual who developed a chemical burn caused by a single topical application of apple cider vinegar containing 5% acetic acid to the skin (91662). Another case of chemical burn has been reported for a 14-year-old patient who applied apple cider vinegar to the skin for 3 days to remove a nevi. Symptoms included erythema, irritation, and non-inflammatory skin erosion. Symptoms were treated by applying mupirocin 2% ointment twice a day for several weeks and using sunscreen on the erosion and surrounding skin (93074). In one clinical trial, use of 0.5% apple cider vinegar soaks commonly caused skin irritation. One patient in this study experienced a nonpruritic papular rash, while another patient experienced severe pruritis with burning and erosion (101172). In another report, a female had an apple cider vinegar tablet lodged in the throat for 30 minutes, resulting in tenderness and pain in the larynx and difficulty swallowing for 6 months following the incident. This was thought to be due to the acid content of the tablet (13183).

Renal ...There is one published report of an individual who developed hypokalemia, elevated renin levels, high positive urinary anion gap, and osteoporosis after ingesting apple cider vinegar 250 mL per day for 6 years. The osteoporosis was attributed to buffering of the acute acid load by bone, and the other effects were attributed to significant bicarbonate excretion (31730).

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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, pectin seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, gas, loose stools, and mild cramps.
Serious Adverse Effects (Rare):
All routes of administration: Allergic reactions, including anaphylaxis, in sensitive individuals.

Gastrointestinal ...Orally, pectin alone or in combination with guar gum and insoluble fiber can cause gastrointestinal adverse effects such as mild cramps, diarrhea, gas, and loose stools (12547,15020,92473).

Immunologic ...Orally and topically, pectin may cause allergic reactions in sensitive individuals. In one case, a 7-year-old boy with a history of oral allergy syndrome after consuming a pectin-containing beverage experienced anaphylaxis after taking a citrus bath containing pectin. Allergy testing confirmed sensitivity to pectin (106928).

Pulmonary/Respiratory ...The occupational inhalation of pectin dust can cause asthma (580,581,582,583,584).

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