Mistletoe by Herb Pharm

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.

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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.

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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).

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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).

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