Mistletoe therapy is the therapeutic use of mistletoe (this article discusses mainly the therapeutic use of viscum album or European mistletoe). A main field of use in anthroposophic medicine is the treatment of cancer, there is also nononcological uses for example in rheumatic disorders.
Mistletoe is the general term given to the parasitic and hemi-parasitic tree dwelling members of the family Viscaceae which contains three genera of mistletoe:
History of Clinical Use
European Mistletoe (Viscum Album) is the genus with the most scientific interest. It was used historically in traditional European herbal medicine for non-oncologic conditions including epilepsy, hypertension, and heart failure. In 1917 Rudolf Steiner together with the physician Ita Wegman developed and used extracts of mistletoe successfully in a case of metastatic breast cancer.
Mistletoe lectins are a member of the type 2 RIP (Ribosomal Inhibitory Compound) family, best known for ricin which has a much less cell specific binding preference and thus potent general toxicity. Lectins are agglutinins, meaning that they have the tendency to cause liquid blood to coagulate into a solid state in their pure form. The coalescing tendency of mistletoe lectins is thought of in Anthroposophic-Goetheanistic thinking to relate to the nerve-sense system (alchemical Sal process) which relates to crystal forming activity, sensing and directing, and in a plant has its orientation in the root. Mistletoe lectins are found in high concentrations in the haustorium, its root equivalent, and have specific tumor apoptotic effects and immunomodulating effects on the human organism. Steiner, long prior to the discovery of mistletoe lectins, gave indications that the mistletoe should be specifically harvested in two harvests, one containing the inner parts of the plant, and the other the outer part, and that these extracts be mixed in a specific way.
Structure of Mistletoe Lectins
Viscum album contains three lectins, differing in their specificity for glycoprotein sites on cell membranes. These are mistletoe lectin 1, 2, and 3 or ML-1, Ml-2, and ML-3. Mistletoe lectin 1 has had the most amount of research. Mistletoe lectins, as members of the type 2 RIP family, are composed of two protein portions linked by a disulfide bond. The A chain is a strong inhibitor of the ribosome, the cellular protein manufacturing organelle. The B chain has strong and selective binding affinity to carbohydrate molecules on the cell surface.
Clinical Effects of Mistletoe Lectins
In tumor cells mistletoe lectins cause apoptosis by inhibiting the ribosomal subunit. In the human body several immune enhancing effects are noteworthy. Leukocytes and granulocytes are upregulated, and it appears that mistletoe lectins are responsible for the increase in eosinophils seen with mistletoe use. Lectins cause the release of the interleukins IL-1 and tumor necrosis factor-α. Dendritic cells, natural killer cells, cytotoxic T cells, and macrophages are upregulated, while T helper cells are modulated in a manner favorable to tumor cell elimination.
Viscotoxins are a 46 amino acid long group of compounds with a net positive charge and 3 disulfide bonds. There are 7 isoforms of viscotoxins from viscum album A1, A2, A3, B, B2, 1-PS and C1, with U-PS being an eighth more distantly related compound. Viscotoxins are hypothesized to interact with phosphatidylserine that is a prominent feature of cancer cells membranes, opening a hole in the cell membrane and destabilizing the DNA. Viscotoxins have been shown to act as an antimicrobial compound, specifically having anti-fungal activity.
Oligosaccharides and Polysaccharides
Mistletoe extracts contain oligosaccharide compounds that have been found to have an immune stimulating effect on natural killer cells. One oligosaccharide HM-BP has been identified in Helixor Mali and enhances natural killer cells through triggering release of interferon gamma.
Depending on the host tree viscum album extracts contain different proportions of phenolic acids. Caffeic, salicylic (primarily from willow host tree), ferulic, and rosmarinic (mostly from apple host tree) acid are found in varying amounts. Mistletoe growing on the ash tree (Abnoba fraxini) has the highest overall amount of polyphenolic compounds. This quercetin family of compounds exerts apoptotic influences on tumor cells and antioxidant, anti inflammatory, and and pain relieving effects clinically.
Triterpine compounds have been isolated from mistletoe extracts. Betulinic acid is isolated from birch host tree mistletoe and exerts a multitude of anticancer effects, regulating JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and ubiquitination pathways in tumor cells. Other triterpenes isolated from mistletoe extracts are b-amyrin acetate and oleanolic acid. As these are poorly water soluable the manufacturers use extraction techniques to enhance these compounds in their extracts.
There have been several peer reviewed studies on the safety of viscum album extracts. These have all shown that mistletoe therapy is safe in a variety of routes (subcutaneous, intravenous, intralesional, and intrathecal) as well as doses, and along with many types of conventional modalities.
- A US based study led by Johns Hopkins looked at the safety of intravenous Helixor viscum album extracts in stage 4 cancer patients heavily pretreated with chemotherapy. It concluded "Intravenous mistletoe demonstrated manageable toxicities with disease control and improved Quality of Life in a heavily pretreated solid tumor population."
- A 2017 phase 1 dose escalation trial of intravenous mistletoe found that "weekly infusions of 2000 mg of the pine-mistletoe extract were tolerated and can be used in further studies but had a risk for allergic reactions and fever."
- A 2018 randomized controlled study looked at breast cancer patients treated with subcutaneous Iscador or Helixor compared to controls. Both arms received conventional dosed chemotherapy with cyclophosphamide, adriamycin, and 5-fluorouracil. The study found that "Mistletoe extracts were safe in this clinical study... mistletoe extracts had no adverse interactions with the anticancer agents used in this study. Furthermore, certain side effects of chemotherapy decreased under this complementary treatment in breast cancer patients."
- A 2011 review of 69 human and 48 animal trials using up to 1500mg of VAE extracts in humans found that "Application of higher dosages of VAE or Mistletoe Lectins is not accompanied by immunosuppression; altogether VAE seems to exhibit low risk but should be monitored by clinicians when applied in high dosages."
- In 2011 a 3-armed randomized, double blind clinical trial looked specifically at IL-6 and CRP production in relationship to mistletoe as there was concern that there may be an unfavorable impact on lymphoma. It concluded "Treatment with (mistletoe) results in eosinophilia and an increase of CD4 cells but not in an increase of IL-6 or CRP. No safety concerns regarding the two mistletoe preparations have been raised by this study."
- A 2014 multicentre, observational study on subcutaneous injection of mistletoe extracts found that there were no serious adverse drug reactions. "The results of this study indicate that mistletoe therapy is safe. Adverse drug reactions were mostly mild to moderate in intensity and appear to be dose-related and explained by the immune-stimulating, pharmacological activity of mistletoe."
- A 2014 observational study on higher dose intravenous mistletoe found that this therapy was generally safe.
- A 2018 safety trial looked at the concurrent use of mistletoe with conventional targeted therapies such as avastin and herceptin. There were 4.1 times less side effects in the viscum album group compared to the control group. "Addition of viscum album to targeted therapy significantly reduced the probability of oncological treatment discontinuation by 70%"
- A 2017 trial found no differences in safety between patients using checkpoint inhibitors alone versus with mistletoe extracts.
- A 2014 in vitro study looked at drug-herb interactions between mistletoe components and common chemotherapy agents and found no danger of drug-herb interactions. "VAE did not inhibit chemotherapy induced cytostasis and cytotoxicity in any of our experimental settings. At higher concentrations VAE showed an additive inhibitory effect."
- A 2018 case series of salvage very high dose viscum album extract in palliative pediatric cancer found some clinical effect and reported safety in a controlled inpatient facility. This study also used intrathecal injection of mistletoe extracts. "Our study underpinned the safety and feasibility of high-dose mistletoe infusion in children with advanced stages of cancer and showed noteworthy antineoplastic effects, which should be verified in a prospective clinical phase II/III-study. Because of possible side effects, the treatment should be implemented only in an in-patient setting in experienced pediatric oncology centers."
- A 2019 study found no additional autoimmunity flares in cancer patients with pre-existing autoimmune conditions. "Our findings suggest that add-on viscum album therapy in cancer patients with preexisting autoimmune diseases as Hashimoto’s thyroiditis, psoriasis, ulcerative colitis, Grave’s disease, and some rheumatic diseases is safe. No higher rates of viscum album associated adverse effects were observed and the overall adverse effect rates were significantly lowered in viscum album therapy periods."
- A 2014 study found that intratumoral injection of mistletoe gave an anticipated amount of local inflammation around the tumor as well as fever. These side effects were generally tolerable and intratumoral mistletoe was found to be safe and the side effects part of the anticancer working of mistletoe. "Intratumoral injection of mistletoe preparations resulted in a relatively high frequency of adverse drug reactions. Nearly all adverse drug reactions were mild to moderate however, and no serious adverse drug reactions occurred. Furthermore, it is possible that immune-related adverse drug reactions such as pyrexia and local inflammatory reactions might be critical for tumor response."
Hypothetical diagram explaining the possible mechanisms of Viscum album extract application on QoL. Büssing, A., Raak, C., & Ostermann, T. (2012). Quality of Life and Related Dimensions in Cancer Patients Treated with Mistletoe Extract (Iscador): A Meta-Analysis. Evidence-Based Complementary and Alternative Medicine : ECAM, 2012, 219402. https://doi.org/10.1155/2012/21940
Büssing et al examined 734 patients treated with subcutaneous Iscador versus 741 controls in 13 controlled trials (9 of which were randomized) and looked at differences in quality of life. Though the included studies suffered from
quality issues such as lacking description of intention to treat analysis, compliance, and enrolled less than 200 patients, most trials were randomized and all of the results pointed to significant quality of life effects, despite high heterogeneity.
Ernst et al 2003
Ernst et al examined 10 randomized controlled trials. They did not perform statistical analysis because of heterogeneity and concluded an overall lack of benefit of mistletoe. Though they did comment on quality issues with the respective trials, 6 of the 10 actually did report a benefit. Edzard Ernst is a well known integrative medicine skeptic, publishing dozens of review articles on integrative modalities from acupuncture to chiropractic all with negative findings.
A 2008 Cochrane review of 21 trials found mistletoe therapy to be generally safe. There were known issues with methodological quality that limited the strength of findings. The review team found weak evidence for survival benefit and stronger for quality of life improvement.
"Of the 16 trials investigating the efficacy of mistletoe extracts for either improving QOL, psychological measures, performance index, symptom scales or the reduction of adverse effects of chemotherapy, 14 showed some evidence of a benefit, but only 2 of them including breast cancer patients during chemotherapy were of higher methodological quality.
Data on side effects indicated that, depending on the dose, mistletoe extracts were usually well tolerated and had few side effects.
The evidence from RCTs to support the view that the application of mistletoe extracts has impact on survival or leads to an improved ability to fight cancer or to withstand anticancer treatments is weak. Nevertheless, there is some evidence that mistletoe extracts may offer benefits on measures of QOL during chemotherapy for breast cancer, but these results need replication."
Kienle et al 2009
Kienle et al performed a systematic review of preclinical and clincal trials on mistletoe's role in helping treat breast and gynecological cancers in a total of nearly 10,000 patients. In terms of 22 trials assessing survival survival they found "12 reported a statistically significant benefit, the others either a trend or no difference. 3 RCTs and 6 non-RCTs assessed tumour behaviour (remission or time to relapse); 3 reported statistically significant benefit, the others either a trend, no difference or mixed results." Quality of life and tolerability of treatments were also assessed in "15 RCTs and 9 non-RCTs. 21 reported a statistically significant positive result, the others either a trend, no difference, or mixed results." Though trial methodology was a concern, some trials, especially more recent ones, were of good quality. A review of preclinical studies and animal trials found that "VAE and its compounds have strong cytotoxic effects on cancer cells." Kienle et al found that mistletoe therapy was generally well tolerated and safe.
Specific Cancer Types
Non Small Cell Lung Cancer
Effects on the Immune System
Quality of Life
Decreased Side Effects from Chemotherapy
Current Clinical Trials
As of March 2023 a phase 3 randomized trial is recruiting for patients with superficial bladder cancer. One arm will receive instillations of abnoba mistletoe into their bladder and compared with the chemotherapy mitomycin c.
A phase 2, single arm study of osteosarcoma patients with fully resected pulmonary metastases will be conducted at University of Texas MD Anderson Cancer Center. Participants will receive Iscador® Pini as a prophylactic immunotherapy. This trial replicates in part the 2007 two armed study of post relapse disease free survival in fully resected osteosarcoma. One arm receiving etoposide had an average survival of 7 months (all had recurrence) and the other receiving Iscador Pini had a median survival of 106 months (5 out of 9 without recurrence).
A Phase 1, dose finding trial is being conducted on Iscador Pini in Israel. 
Currently there are four companies that extract mistletoe: Abnoba, Helixor, Iscador, and Iscucin. They each use refined extraction and preparation techniques and use extracts of mistletoe from different host trees. Their final products vary greatly in concentration of lectins and viscotoxins as well as host tree specific compounds.
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- Vademecum of Anthroposophic Medicines. Best Practices for Mistletoe Use in Cancer Care (4th ed.). Society of Anthroposophic Doctors in Germany. 2019. ISBN 978-3-946951-06-3.
- Anthromedics: Principles and Application of Mistletoe Therapy in Oncology: https://www.anthromedics.org/PRA-0897-EN
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