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POSSIBLY INEFFECTIVE

• Head and neck cancer. Subcutaneous European mistletoe extract does not seem to improve survival in patients with head and neck cancer. Oral European mistletoe has not been evaluated for this use. Details: A large clinical trial in patients with head and neck squamous cell carcinoma shows that subcutaneous administration of European mistletoe extract before or after surgery or radiation does not improve overall survival or disease-free survival when compared with surgery or radiation alone (8842).
• Melanoma. Subcutaneous European mistletoe extract does not seem to improve long-term survival rates in patients undergoing surgery for stage II or III melanoma. Oral European mistletoe has not been evaluated for this use. Details: A phase III clinical trial in patients with stage II or III melanoma undergoing surgical removal of lesions and positive lymph nodes shows that subcutaneous administration of a specific European mistletoe extract (Iscador M) does not improve disease-free interval or overall survival over a period of 8 years when compared with observation alone (24780).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bladder cancer. It is unclear if subcutaneous or intravesical European mistletoe extract is beneficial in patients with bladder cancer. Oral European mistletoe has not been evaluated for this use. Details: One small clinical study in patients who have had transurethral resection for superficial urothelial bladder carcinoma shows that intravesical administration of a specific European mistletoe extract 50 mL, containing mistletoe lectin 10 ng/mL to 5000 ng/mL, weekly for 6 weeks might reduce bladder cancer recurrence rates at 12 months, with similar rates to those observed with bacillus Calmette-Guerin (BCG) therapy (15258). Also, a small retrospective chart review of patients with recurrent bladder cancer has found that subcutaneous administration of a specific European mistletoe extract (Iscucin Salicis, Wala Heilmittel GmbH) for several months might be associated with reduced tumor recurrence and an increased duration of tumor-free periods (93268).
• Breast cancer. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with breast cancer. Oral European mistletoe has not been evaluated for this use. Details: Observational research in patients with solid tumors of the breast has found that subcutaneous administration of certain specific European mistletoe extracts (Iscador, Weleda; Helixor, Helixor Heilmittel GmbH & Co. KG) is associated with reduced tumor progression and improved survival when compared with a control (7045,15351,24798). However, these findings were not replicated in a randomized, controlled study. A small clinical trial in patients with breast cancer receiving chemotherapy shows that subcutaneous injection of European mistletoe extracts (Helixor A, Iscador M Spez) three times weekly for 18 weeks does not reduce the rate of relapse or metastasis or improve quality of life when compared with chemotherapy alone (99497).
• Cancer. A meta-analysis of several small, low-quality clinical studies suggests that subcutaneous European mistletoe extract might improve quality of life in some patients with cancer. Oral European mistletoe has not been evaluated for this use. Details: Several small clinical studies have assessed the impact of various European mistletoe extracts (PS76A2, Helixor, Isorel, Eurixor, and AbnobaViscum Quercus), given subcutaneously either alone or with chemotherapy, on quality of life in patients with various types of cancer (24777,24782,24786,24788,24803,24804,93259,93260,93262,93269). A meta-analysis of these and many other small clinical studies shows that subcutaneous administration of European mistletoe extract has a moderate effect on overall quality of life when compared with a control group, with significant improvements on various subdomains. A larger effect size is observed with more recent trials; however, this may be due to the inclusion of patients with less severe disease in more recent studies when compared with earlier studies (105839). The validity of these findings is limited by the high risk of bias of most of the included studies and the heterogeneity of the studies and patient populations.
• Cancer-related fatigue. A meta-analysis of several low-quality studies suggests that subcutaneous European mistletoe extract might improve fatigue in some patients with cancer. Oral European mistletoe has not been evaluated for this use. Details: A meta-analysis of 12 mostly small, unblinded randomized studies in 1525 patients with a variety of cancers shows that various European mistletoe extracts (e.g., Abnobaviscum, Eurixor, Helixor, Iscador, Lektinol) given subcutaneously at undefined doses modestly improves patient-reported fatigue scores when compared with placebo or usual care (110441). This report also describes a meta-analysis of 7 mostly large nonrandomized, retrospective studies in the same patient population. This analysis suggests that various European mistletoe extracts given subcutaneously may modestly improve clinician-reported fatigue when compared with usual care (110441). The validity of these findings is limited by the low quality and heterogeneity of the included studies.
• Chemotherapy-induced diarrhea. It is unclear if subcutaneous European mistletoe extract can reduce the rate of chemotherapy-induced diarrhea. Oral European mistletoe has not been evaluated for this use. Details: A small clinical study in patients with gastric cancer recovering from surgery and receiving chemotherapy with doxifluridine shows that subcutaneous administration of a specific European mistletoe extract (Abnobaviscum Quercus, Abnoba GmbH) three times weekly for 24 weeks reduces the risk of chemotherapy-induced diarrhea by 86% when compared with doxifluridine alone (93262).
• Colorectal cancer. Several small, low-quality clinical and observational studies suggest that subcutaneous administration of specific European mistletoe extracts may improve survival or tumor response in patients with colorectal cancer when used as adjunct therapy. Oral European mistletoe has not been evaluated for this use. Details: One small clinical study in patients with solid tumors of the colon shows that subcutaneous administration of a specific European mistletoe extract (Iscador, Weleda) increases survival time when compared with matched controls not receiving European mistletoe (7045). Another small clinical study in patients with advanced colorectal cancer shows that infusions of another specific European mistletoe extract (Isorel, Novipharm GmbH), in combination with chemotherapy and surgery, improves survival by at least 38% when compared with chemotherapy plus surgery or surgery alone (24783). Other small clinical studies in patients with colorectal cancer show that subcutaneous administration of another specific European mistletoe extract (Helixor, Helixor Heilmittel GmbH & Co. KG) 100-200 mg three times weekly, in addition to chemotherapy, nearly doubles survival over 2 years when compared with chemotherapy alone; however, between-group differences in tumor progression were not observed (24785,24789). Additionally, a small observational study in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy shows that subcutaneous administration of a specific European mistletoe extract (Abnobaviscum Quercus, Abnoba GmbH) 0.02 mg three times weekly for three weeks, and then slowly titrated up to 20 mg three times weekly for a total of 24 weeks, improves tumor response rates when compared with chemoradiotherapy alone (107285). Despite these promising results, much research in this field suffers from poor study design (10672).
• Common cold. It is unclear if subcutaneous European mistletoe extract can prevent the common cold. Oral European mistletoe has not been evaluated for this use. Details: One small clinical study in healthy individuals shows that subcutaneous administration of a specific European mistletoe extract (Iscador P or Iscador Qu, Weleda) twice weekly for 12 weeks does not reduce the frequency or duration of the common cold when compared with placebo (24806).
• Epilepsy. Although there has been interest in using oral European mistletoe for epilepsy, there is insufficient reliable information about the clinical effects of European mistletoe for this purpose.
• Gastric cancer. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with gastric cancer. Oral European mistletoe has not been evaluated for this use. Details: One small clinical study in patients with solid tumors of the stomach shows that subcutaneous administration of a specific European mistletoe extract (Iscador, Weleda) improves survival when compared with matched controls not receiving European mistletoe (7045). Another small clinical study in patients with gastric cancer recovering from surgery shows that subcutaneous administration of a different European mistletoe extract (Abnobaviscum Quercus, Abnoba GmbH) three times weekly for 24 weeks plus chemotherapy improves quality of life, increases total white blood cell and eosinophil counts, and reduces the risk of chemotherapy-induced diarrhea by 86% when compared with chemotherapy alone. However, there is no effect on lymphocyte responses (93262). Much research in this field suffers from poor study design (10672).
• Hepatitis C. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with chronic hepatitis C. Oral European mistletoe has not been evaluated for this use. Details: While a small case series of patients with chronic hepatitis C has found that subcutaneous injection of a specific aqueous extract of European mistletoe (Iscador Qu, Weleda) may decrease viral load and improve quality of life (9770), a small observational study in patients with chronic hepatitis C has found that subcutaneous administration of a different European mistletoe product (Abnobaviscum Quercus, Abnoba GmbH) three times weekly for 6 months does not normalize viral load or liver enzymes, but is associated with improved disease-related symptoms, when compared to baseline (24805). The validity of the findings from these studies is limited by their retrospective nature and lack of a control group.
• Hypertension. Although there has been interest in using oral European mistletoe for hypertension, there is insufficient reliable information about the clinical effects of European mistletoe for this purpose.
• Kidney Transplant. It is unclear if retroperitoneal instillation of European mistletoe extract is beneficial in kidney transplant patients with significant postoperative lymphatic drainage. Oral European mistletoe has not been evaluated for this use. Details: A large retrospective chart review in hospitalized kidney transplant patients with a large amount of postoperative lymphatic drainage suggests that retroperitoneal instillation of European mistletoe extract (Helixor M) 100 mg via the drainage tube may reduce drainage by about 83 mL from postoperative days 7 to 14 and decrease the length of hospitalization when compared with usual care (110442) The validity of these findings is limited by the retrospective study design.
• Leukemia. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with leukemia. Oral European mistletoe has not been evaluated for this use. Details: A small clinical study in patients with chronic myeloid leukemia shows that subcutaneous administration of a specific European mistletoe extract (Helixor) at doses up to 350 mg increases survival by up to 25.7 months when compared with survival times previously published in the scientific literature (24781). The validity of this finding is limited by the lack of a randomized comparator group.
• Lung cancer. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with lung cancer. Oral European mistletoe has not been evaluated for this use. Details: Observational research in patients with non-small cell lung cancer (NSCLC) has found that subcutaneous administration of European mistletoe extracts (Abnobaviscum, Helixor, and Iscador) along with chemotherapy is associated with increased survival in patients with stage IV NSCLC, but not stage I-IIIA NSCLC, when compared with chemotherapy alone (99498,105840). Additionally, a small, randomized clinical study in patients with NSCLC shows that treatment with a specific European mistletoe extract (Iscador) does not significantly increase median survival time or tumor response when compared with placebo (24784,24790).
• Malignant pleural effusions. It is unclear if intrapleural European mistletoe extract is beneficial in patients with malignant pleural effusions. Oral European mistletoe has not been evaluated for this use. Details: A small clinical study in patients with malignant pleural effusions shows that intrapleural administration of a specific European mistletoe extract (Helixor M; Helixor Heilmittel GmbH & Co. KG) 100 mg, repeated every other day up to 5 times with doses increased by 100 mg with each successive procedure, increases response rate when compared with doxycycline. The response rate, defined as the percentage of patients who achieved complete or partial response, was 91% with European mistletoe extract and 67% with doxycycline (24774). Another small clinical study in patients with lung cancer and malignant pleural effusions shows that intrapleural administration of this same European mistletoe extract and dosing regimen leads to a one-month pleural effusion recurrence rate of 48% (102547). The validity of this findings if limited by a lack of control group.
• Osteosarcoma. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with osteosarcoma. Oral European mistletoe has not been evaluated for this use. Details: A small, open-label clinical study in patients with complete surgical remission following a second osteosarcoma relapse shows that subcutaneous administration of a specific European mistletoe extract (Iscador P), 3 times weekly for 12 months, improves post-relapse disease-free survival when compared with oral etoposide 50 mg/m2 daily for 21 days of each 28-day cycle for 6 cycles. After one year, 5 of 9 patients who completed treatment with European mistletoe extract had not relapsed, compared with 3 of 10 patients who completed etoposide therapy (105854). In a follow-up report, after a median of 83 months, disease-free survival remained the same in those receiving European mistletoe extract, whereas 0 of 10 patients remained disease-free after completion of etoposide treatment (105837).
• Ovarian cancer. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with ovarian cancer. Oral European mistletoe has not been evaluated for this use. Details: A small observational study in patients with ovarian cancer has found that subcutaneous administration of a specific European mistletoe extract (Iscador) along with conventional therapy is associated with improved survival by more than one year when compared with conventional therapy alone (93260).
• Pancreatic cancer. It is unclear if subcutaneous or intratumoral European mistletoe extract is beneficial in patients with pancreatic cancer. Oral European mistletoe has not been evaluated for this use. Details: Some observational research in patients with stage IV pancreatic cancer has found that subcutaneous administration of European mistletoe extract is not associated with improved rates of partial or complete remission (3707,8848). However, another observational study in patients with inoperable pancreatic cancer being treated with chemotherapy and palliative surgical interventions has found that intratumoral administration of European mistletoe (Helixor, AbnobaViscum, and/or Iscucin) is associated with improved survival when compared with historical survival rates in patients receiving chemotherapy alone (93264). Additionally, a small, open-label clinical study in patients with stage III or IV pancreatic cancer who are no longer eligible for chemotherapy shows that subcutaneous administration of a specific European mistletoe extract (Iscador Qu spezial) at doses starting at 0.01 mg and titrated up to 10 mg three times weekly for up to 12 months increases survival by about 2 months when compared with supportive care alone (93267).
• Radiation exposure. It is unclear if subcutaneous European mistletoe extract is beneficial in children with radiation exposure. Oral European mistletoe has not been evaluated for this use. Details: A small clinical study in children with recurrent respiratory infections due to exposure to ionizing radiation from the Chernobyl nuclear accident shows that subcutaneous administration of a specific European mistletoe extract (Iscador) at doses ranging from 0.001 mg twice weekly to 1 ng/kg twice weekly for 5 weeks reduces the frequency of recurrent respiratory infections by 73% to 78% and improves symptoms such as fatigue, sweating, headache, joint pain, emotional instability, and muscle pain when compared to baseline (24779). The validity of these findings is limited by the lack of a comparator group.
• Uterine cancer. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with uterine cancer. Oral European mistletoe has not been evaluated for this use. Details: A small observational study in patients with uterine cancer has found that subcutaneous administration of a specific European mistletoe extract (Iscador) is associated with improved survival when compared with matched controls (24794). More evidence is needed to rate European mistletoe for these uses.

(Read more about EUROPEAN MISTLETOE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angina. It is unclear if oral hawthorn is beneficial in patients with angina. Details: Preliminary clinical research in patients with angina taking chronic beta-adrenergic receptor blockers or ACE inhibitor therapy shows that taking a hawthorn (Crataegus pinnatifada) extract 100 mg orally three times daily for four weeks improves angina and electrocardiogram (ECG) findings and reduces nitroglycerin intake when compared with placebo (19242). Other preliminary clinical research in patients with unstable angina shows that taking hawthorn 10 grams and hu zang 15 grams orally daily for 4 weeks does not reduce the frequency of angina pectoris attacks when compared with control. However, taking hawthorn and hu zang improved some subjective symptom scores and quality of life scores (109610).
• Anxiety. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in adults with mild to moderate generalized anxiety shows that taking a specific product (Sympathyl, not available in the US) containing hawthorn, magnesium, and California poppy for 90 days modestly improves anxiety scores when compared with placebo (12583). Also, a clinical study in adults with adjustment disorder and anxious mood shows that hawthorn, in combination with black horehound, passion flower, valerian, kola nut, and guarana, modestly improves anxiety scores when compared with placebo (6250). It is unclear if these effects are due to hawthorn, other ingredients, or the combination. Another small clinical study in healthy adults shows that taking a combination of herbal extracts containing hawthorn, passionflower, ballota, and valerian root daily for 14 days reduces subjective anxiety and objective sympathetic and autonomic nervous system activation in response to a psychosocial stressor when compared with placebo (111222). It is unclear if these effects are due to hawthorn, other ingredients, or the combination.
• Arrhythmia. Although there has been interest in using oral hawthorn for arrhythmia, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Atherosclerosis. Although there has been interest in using oral hawthorn for atherosclerosis, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Cardiovascular disease (CVD). Although there has been interest in using oral hawthorn for CVD, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Cognitive function. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In a preliminary clinical trial, a single dose of 25 drops of a combination product of D-camphor and hawthorn berry extract (Korodin) was superior to placebo for increasing cognitive performance in elderly female patients as measured by visuomotor speed and information processing capacity. The active treatment group showed an improvement in attentional and mental performance (19240,91504).
• Congestive heart failure (CHF). The evidence on the effects of oral hawthorn in patients with CHF is conflicting. Although some older research suggests it may be beneficial, more recent, larger studies suggest it may actually increase the risk for complications. Details: There is contradictory evidence about the effects of hawthorn extract in heart failure patients. Several clinical studies show that taking specific hawthorn leaf and flower extracts (LI 132, Faros 300, Lichtwer Pharma; WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals; or HeartCare, Nature's Way) 240-600 mg daily improves ejection fraction and exercise tolerance, reduces subjective symptoms, and decreases the risk of death in patients with New York Heart Association (NYHA) stage II heart failure. In these studies, the maximum effect was usually seen after 6-12 weeks of treatment (8279,8280,11449,19221,19223,19225,19226,19227,19228). Another clinical trial shows that hawthorn extract (WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals or HeartCare, Nature's Way) 1800 mg daily, combined with diuretic therapy, improves exercise tolerance and reduces subjective symptoms in NYHA stage III heart failure. In this study, maximum effect was usually seen after 16 weeks of treatment (8281). In another trial, patients with NYHA II heart failure taking either hawthorn (LI 132, Faros) 300 mg three times daily or captopril 12.5 mg three times daily experienced similar improvements in cardiac performance and symptoms (19230). However, other clinical research suggests no benefit and possible harm with hawthorn. A large-scale clinical trial (SPICE) in patients with NYHA stage II or III heart failure shows that taking specific hawthorn extracts (WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals; HeartCare, Nature's Way) 900 mg daily for 24 months, in combination with conventional treatment, does not decrease hospitalization due to progressive heart failure, non-fatal myocardial infarction, or cardiac death (17203). Another clinical trial in patients with NYHA stage II or III heart failure shows that taking these same specific hawthorn extracts at the same dose for up to 6 months does not slow the progression of heart failure when compared with placebo (19222). In a retrospective analysis of this study, it was shown that heart failure progression was significantly increased in patients taking hawthorn when compared with placebo. The rate of death was also increased by 1.7% over placebo, and heart failure-related hospitalizations increased by 8% over placebo in patients treated with hawthorn (16824).
• Hyperlipidemia. Although there has been interest in using oral hawthorn for hyperlipidemia, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Hypertension. It is unclear if oral hawthorn is beneficial for lowering blood pressure. Details: One preliminary clinical trial showed that taking hawthorn standardized extract 1,000-2,500 mg daily for three days does not significantly reduce blood pressure in hypertensive or prehypertensive patients when compared with placebo (19244). However, another study in patients with diabetes and hypertension shows that taking a specific hawthorn extract (LI 132) 1,200mg daily for 16 weeks significantly decreased diastolic, but not systolic, blood pressure when compared with placebo (19245).
• Orthostatic hypotension. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in older adults with orthostatic hypotension shows that taking a specific combination product containing hawthorn and camphor (Korodin Herz-Kreislauf-Tropfen) 25 drops orally three times daily for 7 days attenuates the blood pressure reduction upon standing when compared with placebo. Signs and symptoms of orthostatic hypotension such as dizziness, blurry vision, and falls also seem to be reduced when compared with baseline (39614,39617). A meta-analysis of 4 studies shows that giving single doses of 20-25 drops of the same combination product increases systolic and diastolic blood pressure when compared with placebo (103620). However, the studies have methodologic problems and, while 2 were conducted in females with orthostatic hypotension, the others involved health young adults or normotensive elderly subjects. The effect of hawthorn alone for treatment of orthostatic hypotension has not been determined. The combination product used in these studies is not available in the US. More evidence is needed to rate hawthorn for these uses.

(Read more about HAWTHORN)

There is insufficient reliable information available about the effectiveness of linden.

(Read more about LINDEN)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dyspepsia. Oral olive leaf extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in healthy adults shows that taking a specific combination product containing olive leaf extract 24% and prickly pear cactus 33% (Mucosave, Bionap S.R.L.) 400 mg daily for 8 weeks seems to improve dyspepsia and other gastrointestinal symptoms when compared with placebo (105904). It is unclear if this benefit would occur in patients with clinically diagnosed dyspepsia.
• Exercise-induced respiratory infections. It is unclear if oral olive leaf extract is beneficial for reducing respiratory infections from exercise. Details: A small clinical study in high school athletes shows that taking one tablet of olive leaf extract providing eleuropein 100 mg daily for 2 months during training season does not reduce the incidence of the common cold when compared with placebo. While it may reduce the number of sick days by 28%, a sub-group analysis suggests that this reduction is only evident in female athletes (101860).
• Gastroesophageal reflux disease (GERD). Although there is interest in using oral olive leaf for GERD, there is insufficient reliable information about the clinical effects of olive for this condition.
• Herpes zoster (shingles). Although there is interest in using oral olive leaf for shingles, there is insufficient reliable information about the clinical effects of olive for this condition.
• Influenza. Although there is interest in using oral olive leaf for influenza, there is insufficient reliable information about the clinical effects of olive for this condition.
• Metabolic syndrome. It is unclear if oral olive leaf extract is beneficial for improving body composition and cardiovascular risk factors in patients with metabolic syndrome. Details: A small clinical trial in overweight, middle-aged males at risk for metabolic syndrome shows that taking four capsules of olive leaf extract providing oleuropein 51.1 mg and hydroxytyrosol 9.7 mg daily for 12 weeks improves insulin sensitivity by 15% when compared with placebo. However, body composition, blood pressure, cholesterol levels, and other cardiovascular risk factors were not improved (92245).
• Osteoarthritis. It is unclear if oral olive fruit or leaf extract is beneficial for improving osteoarthritis. Details: Preliminary clinical research shows that taking a freeze-dried aqueous extract of olive fruit 400 mg daily for 8 weeks decreases pain and increases mobility in people with osteoarthritis (14844). Other preliminary clinical research in adults with knee osteoarthritis shows that taking olive leaf extract 50.1 mg daily for 4 weeks improves overall pain measurements by 14%, compared to only 4% in the placebo group. However, many individual measurements of pain are not improved (92252).
• Osteoporosis. It is unclear if oral olive leaf extract is beneficial for osteoporosis. Details: Clinical research shows that taking olive leaf extract (Bonolive, BioActor BV) 250 mg daily for 12 months, along with elemental calcium 400 mg daily, increases osteocalcin levels by about 32% when compared to baseline; this increase was significant when compared to those taking calcium 400 mg plus placebo, who showed a 6% decrease in osteocalcin levels. However, taking olive leaf extract does not significantly increase bone mineral density of the lumbar spine or femur neck when compared with placebo (92247).
• Rheumatoid arthritis (RA). It is unclear if oral olive fruit extract is beneficial for improving RA symptoms. Details: Preliminary clinical research in adults with RA shows that taking an aqueous freeze-dried extract of olive fruit 400 mg daily for 8 weeks does not improve symptoms when compared with control (14844). More evidence is needed to rate the effectiveness of olive for these uses.

(Read more about OLIVE)

POSSIBLY EFFECTIVE

• Obesity. Oral Phaseolus vulgaris extract may reduce body weight and waist circumference in overweight and obese adults. Details: A meta-analysis of 6 small clinical studies shows that taking Phaseolus vulgaris extract daily for 4-12 weeks reduces body weight by around 1.6% when compared with placebo (107439). While some small studies show conflicting findings (12186,26158), most research in overweight and obese adults suggests that taking white kidney bean extract 800-1000 mg or cranberry bean extract 100 mg three times daily for 5-12 weeks reduces body weight by 1.5-4 kg, body mass index by about 0.7 kg/m2, and waist circumference by about 1.5-5 cm when compared with placebo or other control (26156,29926,93075,93077,104875). Specific products evaluated include Phase 2 (Pharmachem Labs; also marketed as Starchlite and Phaselite) (26156,29926); Carb Intercept with Phase 2 (Natrol LLC) (93075); and Beanblock (Indena S.p.A) (93077). Phaseolus vulgaris extract has also been evaluated in combination with other ingredients, with modestly positive results. These combination products include Blokcal (Pharmachem Labs) containing white kidney bean extract (Phase 2, Pharmachem Labs) 445 mg daily and elemental chromium 50-60 mcg daily for 30 days (15518); Suco-Bloc (Med-Eq), containing white kidney bean extract (Phaseolamin, Leuven Bioproducts) 200 mg, inulin from chicory root (Raftiline, Orafti SA) 200 mg, and garcinia extract 50 mg per tablet, 2 tablets three times daily with meals for 12 weeks (26157); Phaseolamin 1600 diet (Metabolic Inc.), containing the Phaseolus vulgaris constituent phaseolamin 750 mg with clove 200 mg, lysine 20 mg, arginine 20 mg, and alanine 20 mg, taken in two divided doses daily for 8 weeks (93076); and Bonvit (Indena), containing Phaseolus vulgaris extract 100 mg and artichoke 200 mg three times daily for 8 weeks (93080).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Colorectal cancer. It is unclear if oral Phaseolus vulgaris is beneficial for the prevention of colorectal cancer recurrence. Details: Observational research has found that dietary intake of several varieties of Phaseolus vulgaris, including baked beans, kidney beans, pinto beans, lima beans, and navy beans, is inversely associated with the risk of advanced colorectal adenoma recurrence. Results from the study show that the odds for advanced adenoma recurrence is 65% lower for patients who consume higher amounts of Phaseolus vulgaris when compared with those who consume lower amounts (29922).
• Diabetes. Small clinical studies suggest that oral Phaseolus vulgaris may not improve postprandial glucose levels in patients with type 2 diabetes. Details: While results from some small clinical studies in patients with type 2 diabetes suggest that taking Phaseolus vulgaris extract or consuming Phaseolus vulgaris beans can reduce postprandial glucose levels, most studies, including a meta-analysis of 6 small clinical trials, show that Phaseolus vulgaris does not significantly reduce postprandial glucose when compared with placebo or other control (93078,107439). Another small clinical study in patients with type 2 diabetes shows that taking 15 grams of a combination of Phaseolus vulgaris pod, white mulberry, and bilberry three times daily for 2 months decreases blood glucose by up to 24% when compared with baseline (33943). It is unclear if these findings are due to Phaseolus vulgaris, other ingredients, or the combination. Additionally, the validity of these findings is limited by the lack of a control group.
• Hypercholesterolemia. Oral Phaseolus vulgaris has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small, open-label clinical study in overweight and obese patients shows that taking Phaseolus vulgaris (white kidney bean) extract 300-600 mg plus carob gum extract 50-100 mg three times daily for 3-9 months modestly reduces total cholesterol levels and increases excretion of fat in the feces when compared to baseline (10633). The validity of these findings is limited by the lack of a comparator group.
• Kidney stones (nephrolithiasis). It is unclear if oral Phaseolus vulgaris extract is beneficial in patients with kidney stones. Details: A small clinical study in adults with small kidney stones shows that taking a Phaseolus vulgaris extract made from 250 grams of green beans three times a week for 6 weeks modestly reduces the size of kidney stones and lowers urinary calcium and oxalate levels when compared with a control group (104874).
• Lung cancer. It is unclear if oral Phaseolus vulgaris is beneficial for the prevention of lung cancer. Details: Observational research has found that consuming higher amounts of dietary phytoestrogens, such as isoflavones from Phaseolus vulgaris beans and soy, is associated with a 44% to 72% lower risk of developing lung cancer when compared with consuming lower amounts. The beneficial effect appears to be more pronounced in males than females (13190).
• Myocardial infarction (MI). Although there has been interest in using oral Phaseolus vulgaris for the prevention of MI, there is insufficient reliable information about the clinical effects of Phaseolus vulgaris for this purpose.
• Urinary tract infections (UTIs). Although there has been interest in using oral Phaseolus vulgaris for UTIs, there is insufficient reliable information about the clinical effects of Phaseolus vulgaris for this purpose. More evidence is needed to rate Phaseolus vulgaris for these uses.

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POSSIBLY SAFE ...when used orally, subcutaneously, or intravenously and appropriately. There is some evidence that European mistletoe extracts can be used safely (7039,9769,15351,24773,24778,93261,93266,93267,96487,107285). However, they have a narrow therapeutic range; high doses are not safe. Tell patients not to consume more than three mistletoe berries or two leaves (12). Advise patients not to use European mistletoe for self-medication.

LIKELY UNSAFE ...when used orally in high doses. Ingestion of high doses of mistletoe berry or leaf can cause serious adverse reactions. More than three berries or two leaves can cause seizures, bradycardia, hypotension, and death (7039).

PREGNANCY: LIKELY UNSAFE
when used orally or subcutaneously. European mistletoe might have uterine stimulant and abortifacient activity (19).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about EUROPEAN MISTLETOE)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Hawthorn preparations in doses of up to 1800 mg daily seem to be safe when used for up to 16 weeks. Although hawthorn might be safe for long-term use, current studies have not evaluated safety past 16 weeks (8279,8280,8281,10144,17203,104689). There is insufficient reliable information available about the safety of hawthorn when used topically.

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

(Read more about HAWTHORN)

LIKELY SAFE ...when linden leaf is used orally and appropriately in amounts normally found in foods (12). Linden leaf has Generally Recognized as Safe (GRAS) status in the US (4912). There is insufficient reliable information available about the safety of linden when used orally or topically in medicinal amounts.

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

(Read more about LINDEN)

LIKELY SAFE ...when olive fruit is used orally and appropriately in amounts commonly found in foods.

POSSIBLY SAFE ...when olive leaf extract is used orally and appropriately. Olive leaf extract providing 51-100 mg oleuropein daily has been used with apparent safety for 6-8 weeks (92245,92247,101860). There is insufficient reliable information available about the safety of olive fruit extract when used in amounts greater than those found in foods.

PREGNANCY AND LACTATION:
Insufficient reliable information available; stick with amounts commonly found in foods.

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POSSIBLY SAFE ...when used orally and appropriately. Most research has evaluated a specific Phaseolus vulgaris (white kidney bean) extract (Phase 2, Pharmachem Labs), which appears to be safe in doses of up to 3 grams daily for 2-3 months (12186,15518,26157,29926). Other Phaseolus vulgaris (white kidney bean) extracts also seem to be safe in doses of 0.9-2.4 grams daily when used for up to 3 months (10633,104875).

POSSIBLY UNSAFE ...when large amounts of fresh Phaseolus vulgaris husks are ingested. Raw Phaseolus vulgaris husks contain lectins that can cause gastrointestinal upset. Cooking destroys the lectins (18).

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

(Read more about PHASEOLUS VULGARIS)

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, European mistletoe might increase the risk of hypotension when taken with antihypertensive drugs.  Details Animal research suggests that European mistletoe extracts have hypotensive effects (93270,96492).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, European mistletoe might decrease the effectiveness of immunosuppressants.  Details Clinical and in vitro studies suggest that European mistletoe might have immunostimulant effects (7039,8843,8844,24775,24779).

(Read more about EUROPEAN MISTLETOE)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, hawthorn may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro and animal research shows that hawthorn can inhibit platelet aggregation (95528,95529,95530,95531). However, its effect in humans is unclear. One observational study shows that patients taking hawthorn shortly before undergoing coronary artery bypass graft (CABG) surgery or valve replacement surgery have a 10% incidence of postoperative bleeding, compared with 1% in those who never consumed hawthorn extract (95527). However, clinical research shows that taking a specific preparation of dried hawthorn leaves and flowers (Crataesor, Soria Natural Lab) 800 mg three times daily for 15 days does not affect platelet aggregation or levels of thromboxane B2, the metabolite of thromboxane A2, in healthy humans (54664).

BETA-BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might cause additive effects on blood pressure and heart rate.  Details Some evidence shows that hawthorn might lower blood pressure and heart rate (12595,19245).

CALCIUM CHANNEL BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might cause additive coronary vasodilation and hypotensive effects.  Details Some evidence shows that hawthorn might lower blood pressure due to vasodilatory effects (12595,19245).

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hawthorn might potentiate the effects and adverse effects of digoxin.  Details Hawthorn appears to improve cardiac output (12595); however, hawthorn does not appear to affect digoxin pharmacokinetics (19249).

NITRATES Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might cause additive coronary vasodilatory effects.  Details Some evidence shows that hawthorn might lower blood pressure due to vasodilatory effects (12595,19245).

PHOSPHODIESTERASE-5 INHIBITORS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might result in additive vasodilation and hypotension.  Details Hawthorn might inhibit PDE-5 and cause vasodilation (12595).

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(Read more about LINDEN)

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Phaseolus vulgaris might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Small clinical studies suggest that Phaseolus vulgaris beans or bean pods, ingested alone or along with white mulberry leaf and bilberry, reduce blood glucose levels in some patients with diabetes (29921,29925,33943).

(Read more about PHASEOLUS VULGARIS)

General ...Orally, European mistletoe seems to be well tolerated when used in small amounts. However, a thorough evaluation of safety outcomes has not been conducted. Parenterally, European mistletoe may be safe when administered by a healthcare provider. High oral or parenteral doses may be unsafe.
Most Common Adverse Effects:
Orally: Diarrhea, intestinal cramps, and vomiting at high doses.
Parenterally: Chills, diarrhea, eosinophilia, fever, flatulence, headache, malaise, nausea, pruritus, vomiting, and pain and inflammation at the injection site.
Serious Adverse Effects (Rare):
Orally: Hepatitis, seizures, coma, and death at high doses.
Parenterally: Necrosis at injection site. Allergic reactions, including anaphylaxis, in sensitive individuals.

Cardiovascular ...Subcutaneously, European mistletoe may cause angina and orthostatic circulatory disturbances (7044,7045,9769).

Dermatologic ...Subcutaneously and intravenously, European mistletoe may cause pruritus, skin rash, and angioedema (93261,93265,93266,96476,107285,107286). When administered subcutaneously, the use of an extended dose-escalation regimen may limit the development of localized reactions in comparison to rapid dose escalation (96476).

Endocrine ...Intravenously, aviscumine, a pure form of mistletoe lectin I produced by recombinant DNA techniques, may cause hypokalemia (16385).

Gastrointestinal ...Orally, European mistletoe may cause vomiting, diarrhea, and intestinal cramps (18). Intraperitoneal and intratumoral injection may cause nausea, vomiting, and abdominal pain (7106,93264,96495). Subcutaneously, European mistletoe may cause flatulence, loose stools, diarrhea, nausea, and vomiting (93261,93265). Intravenously, aviscumine, a pure form of mistletoe lectin I produced by recombinant DNA techniques, may cause nausea and vomiting (16385,93261).

Genitourinary ...Intravenously, aviscumine, a pure form of mistletoe lectin I produced by recombinant DNA techniques, may change urinary frequency (16385,93261).

Hematologic ...Subcutaneously, intraperitoneally, or intratumorally, European mistletoe may cause eosinophilia (7044,7045,7106,9769).

Hepatic ...Orally, European mistletoe has been associated with two cases of hepatotoxicity when used in combination with other herbal ingredients. In one case, in which a patient took a combination herbal product, it was deemed unlikely that European mistletoe was the causative agent. It was determined to be most likely due to another ingredient or product contamination (3932). In another case, a previously healthy male presented to the hospital with mild fever, brownish urine, and elevated liver function enzymes after frequent use of European mistletoe extract for 1 month and kudzu root extract for 10 days. Upon discontinuation of the two extracts, liver function slowly returned to normal with no other symptoms (88777). It is unclear if European mistletoe, kudzu, or the combination was responsible for this adverse effect.
Intravenously, aviscumine, a pure form of mistletoe lectin I produced by recombinant DNA techniques, may cause elevated liver enzymes (16385,93261).

Immunologic ...Subcutaneously, European mistletoe may cause allergic reactions (7044,7045,9769) or flu-like symptoms or mild infections (93261). Early research shows that European mistletoe is not associated with an increase in side effects when it is administered in conjunction with targeted cancer treatments such as monoclonal antibodies and immunotherapy regimens, including PD-1/PD-L1 or CTLA-4 inhibitors (96490,96489). There are two case reports of apparent immunologic response to the application of European mistletoe for pleurodesis, resulting in acute respiratory distress and pneumonitis (96488,96494).
There are at least 5 reports of anaphylactic reactions associated with subcutaneous European mistletoe extract (15352,107286). In one case, anaphylaxis did not occur until after 2 years of treatment with European mistletoe (15352). Aviscumine has also been associated with anaphylactic reactions in people who have previously used European mistletoe products (16385).

Musculoskeletal ...Subcutaneous, intratumoral, intraperitoneal, and intravenous administration of European mistletoe can cause pain at the injection site (7044,7045,9769,93264,93266,7106,93261,96495). There is one report of a benign abdominal wall mass developing at the European mistletoe injection site, which was likely the result of a local inflammatory response (15350). Necrosis can also occur at the site of injection (8).

Neurologic/CNS ...Orally, European mistletoe may cause seizures, coma, and death (18). Subcutaneously, European mistletoe can cause headaches (7044,7045,9769,93261,93265) or fatigue or malaise (93261,93265). When injected into the tumor, European mistletoe can cause headaches (93264,96495). Intravenous infusion of aviscumine, a pure form of mistletoe lectin I produced by recombinant DNA techniques, can cause fatigue (16385,93261).

Ocular/Otic ...Orally, European mistletoe may cause contraction of the pupil and uncontrollable eye movement (18). Subcutaneously, European mistletoe may cause dry eyes (93261).

Pulmonary/Respiratory ...There are multiple reports of acute respiratory effects after application of European mistletoe for pleurodesis. In one case, a 52-year-old male presenting with pneumothorax received European mistletoe extract 40 mg (ABNOBAviscum F, ABNOBA Helmittel GmbH) with 50 mL of normal saline into the pleural space. After 3 days, the patient experienced worsening dyspnea with right pleural effusion and bilateral lung infiltration requiring intubation and mechanical ventilation (96488). In another case, a 58-year-old male presenting with postoperative pleural effusion received pleurodesis with European mistletoe extract 500 mg (ABNOBAviscum F) on days 6, 8, 12, and 16 after surgery. Imaging revealed apparent acute respiratory distress and pneumonitis, but without corresponding clinical symptoms, which improved after 5 days of supportive care (96494). In a small retrospective study, 28% of elderly patients with secondary spontaneous pneumothorax who underwent chemical pleurodesis with European mistletoe extract 60 mg (Abnova Viscum-F) in 50 mL of normal saline experienced dyspnea with associated desaturation. These adverse effects were attributed to pain caused by the induced pleural inflammation, and may have also been related to the patients' underlying impaired pulmonary function. Treatment with oxygen via nasal cannula resulted in improvement of symptoms in most patients within 24 hours (105838).

Other ...Subcutaneously, intravenously, and intratumorally, European mistletoe can cause malaise, chills, and high fever (7044,7045,9769,93261,93264,93265,93266,93268,96495,99499). Intravenous infusion of aviscumine, a pure form of mistletoe lectin I produced by recombinant DNA techniques, can cause fever (16385,93261).

(Read more about EUROPEAN MISTLETOE)

General ...Orally, hawthorn seems to be well tolerated when used appropriately. Topically, no adverse effects have been reported, although a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Multiorgan hypersensitivity reactions resulting in acute renal failure have been reported rarely.

Cardiovascular ...Orally, tachycardia (with facial pains) of uncertain relationship to hawthorn was reported in a multicenter clinical trial (54640). Palpitations (19244) were reported in three patients in a large surveillance trial of 3,664 patients with cardiac failure (54692) and in 11 patients with congestive heart failure (CHF) in a literature review of 5,577 patients (19247). Circulation failure has been reported in two patients with CHF in a literature review of 5,577 patients (19247). Incidences of hospitalization, hospitalization due to CHF, worsening of CHF, angina, and atrial fibrillation have also been reported with the use of hawthorn extract WS 1442 (Crataegutt forte), although it is unclear if these events are related to hawthorn supplementation or existing CHF (19222). In clinical trials, chest pain (8281), short-term increases in blood pressure (19240), and other non-specific heart problems (17203) have also been reported following the use of various hawthorn preparations (e.g. WS 1442, Korodin).

Dermatologic ...Orally, erythematous rash has been reported in patients with CHF in a literature review of 5,577 patients (19247). Non-specific rashes and itching (19222,19243) as well as toxiderma from the fruits of hawthorn (54670) have also been reported.

Gastrointestinal ...Orally, rare abdominal discomfort of uncertain relationship to hawthorn has been reported in a large clinical trial, surveillance study, and a literature review (19247,54640,54692). Digestive intolerance (19241), diarrhea (19243), flatulence (8281), gastroenteritis (8281), increased bowel movements (19243), obstipation (8281), mild and rare nausea (10144,19247,19244), nutritional and metabolic problems (17203), and other non-specific gastrointestinal effects (19222), have also been reported. Furthermore, gastrointestinal hemorrhage has been reported in two patients with CHF in a literature review of 5,577 patients (19247).

Musculoskeletal ...In clinical trials, arthritis (8281), back pain (8281), weakness (19243), and other non-specific musculoskeletal effects (19222) have been reported following the use of various hawthorn preparations g. WS 1442, CKBM-A01).

Neurologic/CNS ...Orally, headache and dizziness/vertigo were reported in two patients in a large surveillance trial of 3,664 patients with cardiac failure (54692), in 15 patients with CHF as reported in a literature review of 5,577 patients (19247), and in a varying number of clinical trial participants (8281,19222,19244). Incidences of fainting (19222), fever (17203), and infrequent, mild and transient sleepiness have also been reported (19221,54692).

Psychiatric ...Orally, agitation was reported in a large surveillance trial of 3,664 patients with cardiac failure (54692).

Pulmonary/Respiratory ...Orally, bronchitis has been reported following the use of hawthorn extract WS 1442 (8281).

Renal ...A case of multiorgan hypersensitivity reaction and acute renal failure following the consumption of C. orientalis has been reported (54654).

Other ...Flu-like syndrome (8281) and other non-specific infections have been reported following the use of the hawthorn extract WS 1442 (17203,19222). Hawthorn has also been reported to cause nosebleeds (8281,10144).

(Read more about HAWTHORN)

General ...There is limited information about the adverse effects of linden. Orally, there is one case report of allergic reaction to linden pollen in a linden flower tea (12). Frequent consumption of linden tea is thought to be associated with cardiac damage, but this seems to be rare (6).
Topically, linden extract can cause contact urticaria (12).

Cardiovascular ...Frequent consumption of linden tea is thought to be associated with cardiac damage, but this seems to be rare (6).

Immunologic ...Orally, there is one case report of allergic reaction to linden pollen in a linden flower tea (12). Topically, there is one case report of contact urticaria following the use of a linden extract-containing shampoo (12).

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General ...Orally, olive fruit is well tolerated when used in typical food amounts. Olive leaf extract seems to be well tolerated.
Most Common Adverse Effects:
Orally: Headache and stomach discomfort.

Dermatologic ...Orally, one patient in one clinical trial reported bad skin and acne after using olive leaf extract (101860).

Gastrointestinal ...Orally, three patients in one clinical trial reported stomach ache after using olive leaf extract (101860).

Neurologic/CNS ...Orally, three patients in one clinical trial reported headache after using olive leaf extract (101860).

Psychiatric ...In one case report, a 67-year-old female experienced irritability, anger, a lack of control, and feelings of sadness and negativity after consuming a multi-ingredient product containing olive leaf extract 5 grams, horseradish root, and eyebright daily for 38 days. All psychiatric symptoms disappeared within days of stopping the combined product. It is hypothesized that the hydroxytyrosol component of olive leaf extract contributed to these symptoms due to its chemical similarity to dopamine; however, it is not clear if these symptoms were due to the olive leaf extract or to the other ingredients (96245).

Pulmonary/Respiratory ...Olive tree pollen can cause seasonal respiratory allergy (1543).

(Read more about OLIVE)

General ...Orally, Phaseolus vulgaris extract seems to be well tolerated.
Most Common Adverse Effects:
Orally: Constipation, diarrhea, flatulence, nausea, stomach pain, and vomiting.
Serious Adverse Effects (Rare):
Orally: Hypersensitivity reactions, including anaphylaxis, in sensitive individuals.

Dermatologic ...Topically, Phaseolus vulgaris may cause contact dermatitis in sensitive individuals. A case of occupational contact dermatitis characterized by pruritus, erythema, eczema, and dyspnea has been reported for a 41-year-old farmer who handled the green parts of Phaseolus vulgaris (29920).

Gastrointestinal ...Orally, an extract of the Phaseolus vulgaris variety white kidney bean, as well as alpha-amylase inhibitors isolated from Phaseolus vulgaris, might cause nausea, vomiting, diarrhea, flatulence, constipation, satiety, and stomach pains (11265,18223,29925,104874). Also, white kidney bean extract, taken orally along with carob gum, may cause constipation, flatulence, soft stools, and reduced levels of vitamin B12 and folic acid (10633). Consuming large amounts of raw or undercooked Phaseolus vulgaris beans or extract can cause nausea, vomiting, diarrhea, and gastroenteritis due to the content of phytohaemagglutinin, a plant protein lectin (18223,29916,93082). Cooking usually destroys lectins (18).

Immunologic ...Orally, Phaseolus vulgaris may cause hypersensitivity reactions, including anaphylaxis, in sensitive individuals. A case of severe anaphylactic shock requiring epinephrine and steroid treatment has been reported for a 23-year-old following ingestion of cooked kidney beans, a variety of Phaseolus vulgaris. The causative agents were reported to be phaseolin (vicilin) and phytohaemagglutinin (29918). Also, a case of angioedema resulting from type I hypersensitivity has been reported for a one-year-old child following inhalation of vapors from or ingestion of cooked white beans, another variety of Phaseolus vulgaris (29919).

(Read more about PHASEOLUS VULGARIS)