Premier Digest [Discontinued] by Premier Research Labs

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. 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. Although there has been interest in using oral apple cider vinegar for hyperlipidemia, there is insufficient reliable information about the clinical effects of apple cider vinegar for this condition.
• 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 overweight and obese adults 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).
• 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.

(Read more about APPLE CIDER VINEGAR)

EFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about LACTASE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Celiac disease. Although there has been interest in using oral lipase for celiac disease, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Dyspepsia. It is unclear if oral lipase is beneficial for improving symptoms of postprandial distress syndrome. Details: A small clinical trial shows that taking a specific acid-resistant lipase (Amano Enzyme USA) 280 mg immediately before a high-fat meal does not reduce postprandial bloating and nausea when compared with placebo in individuals with postprandial distress syndrome (101900).
• Inflammatory bowel disease (IBD). Although there has been interest in using oral lipase for IBD, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Prematurity. It is unclear if adding a specific form of lipase, recombinant human bile salt-stimulated lipase (rhBSSL), to infant formula improves outcomes in premature infants. Some research suggests a potential increased risk for adverse effects. Details: Human breast milk contains rhBSSL, but it is inactivated when breast milk is pasteurized for donation. Clinical research in infants born before 32 weeks' gestation shows that adding rhBSSL as 8700 units per 100 mL formula or pasteurized breast milk, for 4 weeks does not increase growth velocity, body length, or head circumference over the next 12 months when compared with formula or pasteurized breast milk devoid of lipase. However, the infants who were small for gestational age (SGA), which made up approximately 15% of the study population, grew by an additional 1.9 grams/kg daily on average when compared with placebo (101940). More evidence is needed to rate lipase for these uses.

(Read more about LIPASE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. Although there has been interest in using oral noni for aging, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Asthma. Although there has been interest in using oral noni for asthma, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Atherosclerosis. Although there has been interest in using oral noni for atherosclerosis, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Athletic performance. It is unclear if oral noni juice is beneficial for athletic performance. Details: Preliminary clinical research shows that drinking 100 mL of a specific juice (Tahitian Noni Juice (TNJ), Tahitian Noni International) containing 89% pureed noni in grapefruit and blackberry juices twice daily for 21 days can increase running time-to-fatigue by approximately 21% in trained distance runners when compared with baseline. Runners taking placebo blackberry juice did not demonstrate improved endurance when compared with baseline (65230).
• Burns. Although there has been interest in using topical noni for burns, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Cancer. It is unclear if oral noni is beneficial in patients with cancer. Details: Preliminary, low-quality clinical research shows that taking noni fruit extract 2-14 grams daily for 28 days does not improve physical function, fatigue, pain, or tumor growth in patients with various forms of advanced cancer when compared with baseline (65173).
• Cardiovascular disease (CVD). Although there has been interest in using oral noni for CVD, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Cataracts. Although there has been interest in using oral noni for cataracts, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Cervical spondylosis. It is unclear if oral noni is beneficial in patients with cervical spondylosis. Details: Preliminary clinical research shows that taking oral noni juice 15 mL twice daily in combination with physiotherapy for 4 weeks can improve neck pain and flexibility scores more than physiotherapy alone in patients with cervical spondylosis. Treatment with noni juice alone was not different than physiotherapy alone. However, the study may have been inadequately powered to detect a difference between these groups (65197).
• Colic. Although there has been interest in using oral noni for colic, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Common cold. Although there has been interest in using oral noni for the common cold, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Cough. Although there has been interest in using oral noni for cough, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Depression. Although there has been interest in using oral noni for depression, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Diabetes. Although there has been interest in using oral noni for diabetes, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Epilepsy. Although there has been interest in using oral noni for epilepsy, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Headache. Although there has been interest in using oral and topical noni for headache, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Hearing loss. It is unclear if oral noni is beneficial for hearing loss. Details: Preliminary clinical research shows that drinking 4 ounces of noni juice daily for 3 months does not improve hearing at most frequencies in hearing-impaired postmenopausal females (65146).
• HIV/AIDS. Although there has been interest in using oral noni for HIV/AIDS, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Hypertension. It is unclear if oral noni is beneficial in patients with hypertension. Details: Preliminary clinical research shows that drinking 4 ounces of a specific noni juice (Tahitian Noni Juice) daily for one month reduces blood pressure by approximately 8% when compared with baseline in individuals with hypertension (65231). The validity of this finding is limited by the lack of a comparator group.
• Insomnia. Although there has been interest in using oral noni for insomnia, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Leishmania lesions. It is unclear if topical noni is beneficial for improving the severity of leishmania lesions. Details: Preliminary clinical research shows that topical application of an ointment containing noni stem extract 1% three times daily for 6 weeks improves leishmania lesion scores when compared with baseline. A good to excellent response was reported in 80% of patients (65174). However, the validity of this finding is limited by the lack of a comparator group.
• Leprosy. Although there has been interest in using topical noni for leprosy, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Liver disease. Although there has been interest in using oral noni for liver disease, there is insufficient reliable information about the clinical effects of noni for this purpose. Additionally, there is some concern that noni might cause hepatotoxicity in some patients.
• Malaria. Although there has been interest in using oral noni for malaria, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Migraine headache. Although there has been interest in using oral noni for migraine headache, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Osteoarthritis. It is unclear if oral noni is beneficial in patients with osteoarthritis. Details: Preliminary clinical research in patients with knee or hip osteoarthritis shows that drinking 3 ounces of a specific noni juice (Tahitian Noni Juice) daily for 90 days can reduce the need for analgesic medications and improve quality of life parameters, including mobility, joint function, social activity, tension level, mood, and the ability to conduct activities of daily living when compared with baseline (65206). However, the validity of this study is limited by the lack of a comparator group.
• Parturition. Although there has been interest in using oral noni for parturition, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Postoperative nausea and vomiting (PONV). It is unclear if oral noni is beneficial in patients with PONV. Details: Preliminary clinical research shows that taking noni fruit extract 600 mg orally one hour prior to surgery reduces postoperative nausea, but not vomiting, in the first 6 hours after surgery by 40% when compared with placebo. However, taking noni fruit extract did not reduce PONV in the first 6-24 hours after the surgery. Taking noni fruit extract 150-300 mg also did not reduce PONV when compared with placebo (17169).
• Premenstrual syndrome (PMS). Although there has been interest in using oral noni for PMS, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Rheumatoid arthritis (RA). Although there has been interest in using oral and topical noni for RA, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Stroke. Although there has been interest in using oral noni for stroke, there is insufficient reliable information about the clinical effects of noni for this purpose.
• Urinary tract infections (UTIs). Oral noni has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some observational research in females with recurrent UTIs has found that taking antibiotics with a combination of noni fruit extract 200 mg, d-mannose 500 mg, and N-acetylcysteine 100 mg orally twice daily for 2 months, then daily for 4 months, may be associated with a lower incidence of recurrent UTI when compared with antibiotics alone. Of patients without a UTI in the first 2 months, 100% of those taking the combination product remained UTI free at 6 months whereas only 6% of those taking antibiotics alone remained UTI free. This combination also seems to improve symptoms of urgency, frequency, and incontinence (97360). It is not clear if these effects are due to noni, other ingredients, or the combination.
• Wound healing. Although there has been interest in using topical noni for wound healing, there is insufficient reliable information about the clinical effects of noni for this purpose. More evidence is needed to rate noni for these uses.

(Read more about NONI)

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

(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

LIKELY SAFE ...when used orally 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.

(Read more about APPLE CIDER VINEGAR)

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

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

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

(Read more about LACTASE)

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

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

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

(Read more about LIPASE)

POSSIBLY SAFE ...when used orally and appropriately. Noni juice has been used in doses of up to 200 mL daily with apparent safely in small clinical studies for up to 3 months (11944,17169,65173). However, there have been several case reports of increased liver enzymes and hepatotoxicity in people taking some noni products (13107,14341,14468,17170,17171,17172). In three reports, hepatotoxicity was linked to a specific brand of noni juice (Tahitian Noni Juice, Tahitian Noni International) (14341,17171). It is unclear if potential contaminants or hypersensitivity reactions may be the cause of these events. More evidence is needed to determine if noni increases the risk for hepatotoxicity. There is insufficient reliable information available about the safety of noni fruit extract when used orally or the safety of noni when used topically.

PREGNANCY AND LACTATION:
While animal research is conflicting on the teratogenic effects of noni (65205,65206), there is insufficient reliable information available about the safety of noni in humans; avoid using.

(Read more about NONI)

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))

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).

(Read more about APPLE CIDER VINEGAR)

(Read more about LACTASE)

(Read more about LIPASE)

ACE INHIBITORS (ACEIs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining noni and ACE inhibitors might increase the risk of hyperkalemia.  Details Noni juice contains significant amounts of potassium, about 6 mEq/100 mL juice (1298). This may increase the risk for hyperkalemia when used in conjunction with ACE inhibitors, which can also increase potassium levels.

ANGIOTENSIN RECEPTOR BLOCKERS (ARBs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining noni and ARBs might increase the risk of hyperkalemia.  Details Noni juice contains significant amounts of potassium, about 6 mEq/100 mL juice (1298). This may increase the risk for hyperkalemia when used in conjunction with ARBs, which can also increase potassium levels.

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, noni may increase the risk of hypotension when used in combination with antihypertensive drugs.  Details Preliminary clinical research suggests that drinking noni juice can reduce blood pressure in individuals with hypertension (65231).

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking noni with hepatotoxic drugs might increase the risk of liver damage.  Details There is concern that noni might cause hepatotoxicity in some patients (13107,14341,14468). Advise patients against combining noni with potentially hepatotoxic drugs.

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking noni fruit juice concomitantly with phenytoin may lower phenytoin levels and increase the risk of seizures.  Details In one case report, an adult taking phenytoin for partial seizures experienced low serum phenytoin levels while taking noni juice 90-200 mL daily. Serum phenytoin levels increased after decreasing noni juice consumption; similarly, serum phenytoin levels decreased after increasing noni juice consumption. Some researchers believe noni juice may induce cytochrome P450 2C9 enzymes, which would decrease phenytoin levels, but this has not been well studied. Patients may need additional monitoring when starting or stopping noni juice supplementation (106057).

POTASSIUM-SPARING DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, combing noni and a potassium-sparing diuretic might increase the risk of hyperkalemia.  Details Noni juice contains significant amounts of potassium, about 6 mEq/100 mL juice (1298). This may increase the risk for hyperkalemia when used in conjunction with potassium-sparing diuretics, which can also increase potassium levels.

RANITIDINE (Zantac) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Taking noni fruit with ranitidine might increase the levels and clinical effects of ranitidine.  Details Clinical evidence shows that taking an aqueous extract of noni fruit 30 minutes prior to taking a single oral dose of ranitidine can increase the rate of absorption and plasma concentration of ranitidine (23387).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking noni juice concomitantly with warfarin might decrease the effectiveness of warfarin.  Details In one case, a 41-year-old patient stabilized on warfarin had a decreased international normalized ratio (INR) following consumption of a specific commercial noni juice product (Noni juice 4 Everything). While the patient was still taking noni juice, an increase in warfarin dose did not produce an increase in INR (14434). However, it should be noted that this particular product contained extracts and derivatives from more than 115 components, many of which contained vitamin K. Furthermore, vitamin K was listed as a separate ingredient of the product, suggesting that the product was possibly fortified with vitamin K. It has not been verified that noni fruit alone contains a significant amount of vitamin K or interacts with warfarin.

(Read more about NONI)

(Read more about PROTEOLYTIC ENZYMES (PROTEASES))

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).

(Read more about APPLE CIDER VINEGAR)

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

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

(Read more about LACTASE)

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

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

(Read more about LIPASE)

General ...Orally and topically, noni seems to be generally well tolerated; however, high quality studies of adverse effects have not been conducted.
Most Common Adverse Effects:
Orally: Abdominal discomfort, nausea.
Serious Adverse Effects (Rare)::
Orally: Hepatotoxicity, including liver failure. However, studies have not conclusively identified whether noni, or contaminants in noni products, were responsible for this toxicity.

Gastrointestinal ...Orally, dehydrated noni fruit has been reported to cause nausea and abdominal discomfort (65173).

Hepatic ...Noni has been associated with several cases of hepatotoxicity in previously healthy patients ranging in age from 14 to 62 years (13107,14341,14468,17170,17171,17172). In two cases, the patients had used a tea or other herbal products containing noni (13107,17172); five had consumed noni juice, specifically Tahitian Noni Juice (Tahitian Noni International) (14341,16648,17171); and two cases involved energy drinks containing several herbal ingredients including noni (17170,90125). Symptoms of liver dysfunction and elevated liver function tests (LFTs) were seen between 2 weeks and 4 months after starting noni. The LFTs started to improve within 2 days of stopping noni and generally normalized within 1 month (13107,14468,17171). Biopsy findings included acute hepatitis, inflammation, hepatocyte necrosis, and hepatocellular cholestasis (14341,17170). One patient, who had a history of prior mild acetaminophen toxicity, had rapidly progressive liver failure after noni ingestion and required transplantation (14341).
Potential product contamination was not ruled out in these case reports. Some researchers theorize that anthraquinones contained in noni could potentially cause hepatotoxicity. Other products containing anthraquinones, such as senna, have been linked to cases of hepatotoxicity. However, analyses of a noni juice product associated with reports of liver damage (Tahitian Noni Juice, Tahitian Noni International) have not detected anthraquinone content (14444). Another analysis of noni fruit puree from which the seeds and skin had been removed had no detectable anthraquinones (92201). However, products containing seed or leaf material had detectable amounts of anthraquinones (92201). The part of the noni plant used might affect hepatotoxicity risk. More evidence is needed to determine if noni causes hepatotoxicity.

(Read more about NONI)

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))