Mistletoe therapy

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Viscum album
Viscum album

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.

Botany

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:

  1. Arceuthobium (Dwarf mistletoe)
  2. Phoradendron (American mistletoe)
  3. Viscum (Mistletoe)[1]

American Mistletoe (Phoradendron serotinum) has a history of use in Mexican and South American traditional medicine for the treatment of cancer.[2]

Clinical Use

A main field of use in anthroposophic medicine is the treatment of cancer, there is also nononcological uses for example in rheumatic disorders.

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.[3]

Bioactive Compounds

Mistletoe Lectins

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.[4] 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.[5] 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.

Viscum album agglutinin (VAA-I) consists of two chains. The A-chain (white) with a molecular weight of 29 kDa and with N-glycosidase activity is a potent ribosomal inactivator. The sugar-binding B-chain (green) with a molecular weight of 34 kDa is responsible for the immunomodulatory effect of the molecule. Red colored parts of the B-chain indicate the sugar-binding receptors. (The picture was kindly provided by Madaus Ag, Germany.) Hajtó, T., Hostanska, K., Berki, T., Pálinkás, L., Boldizsár, F., & Németh, P. (2005). Oncopharmacological perspectives of a plant lectin (Viscum album agglutinin-I): overview of recent results from in vitro experiments and in vivo animal models, and their possible relevance for clinical applications. Evidence-Based Complementary and Alternative Medicine, 2(1), 59–67. Published by Oxford University Press.

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.[6]

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.[7] 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.[8]

Molecular model of viscotoxins opening a pore in the tumor cell membrane
The model that describes the action of viscotoxins against tumor cells. "Frequently cited models for activity of antimicrobial peptides. a AMPs diffusing through solution, b AMPs adsorption to the membrane. After the threshold concentration is achieved, peptide molecules begin to reorient in the lipid bilayer (c). Their further fate may be described using one of three models. The first, depicted in the d is called barrel-stave model. In this scenario, hydrophobic regions of AMPs align with the tails of the lipids and the hydrophilic residues form the inner surface of the forming pore. According to the wormhole model (called also toroidal pore model, shown in e) during peptides aggregation, hydrophilic heads of the lipids are electrostatically dragged by charged residues of AMPs. The membrane bends, two layers merge and form continuous surface surrounding the pore. The carpet model shown in f assumes, that at large concentrations, peptide molecules disrupt the membrane in a detergent-like manner breaking the lipid bilayer into set of separate micelles" from Nawrot, R., Barylski, J., Nowicki, G., Broniarczyk, J., Buchwald, W., & Goździcka-Józefiak, A. (2014). Plant antimicrobial peptides. Folia microbiologica, 59(3), 181–196. https://doi.org/10.1007/s12223-013-0280-4

Viscotoxins

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.[9][10][11] Viscotoxins have been shown to act as an antimicrobial compound, specifically having anti-fungal activity.[12]

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.[13]

Polyphenolic Compounds

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.[14] This quercetin family of compounds exerts apoptotic influences on tumor cells and antioxidant, anti inflammatory, and and pain relieving effects clinically.

Terpenoid Compounds

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.[15] 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.

Scientific Evidence

Cumulative PubMed articles by year with the terms "Mistletoe" and "Cancer"

Safety Trials

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."[16]
  • 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."[17]
  • 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."[18]
  • 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."[19]
  • 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."[20]
  • 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."[21]
  • A 2014 observational study on higher dose intravenous mistletoe found that this therapy was generally safe.[22]
  • 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%"[23]
  • A 2017 trial found no differences in safety between patients using checkpoint inhibitors alone versus with mistletoe extracts.[24]
  • 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."[25]
  • 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."[26]
  • 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."[27]
  • 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."[28]

Meta-analysis

Büssing et al 2012

  • Meta analysis standard mean difference effects showing an overall treatment effect at SMD = 0.56 (CI: 0.41 to 0.71, P < .0001), indicating a moderate effect.

  • 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.[29] 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.[30] 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.[31]

Cochrane Review

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."[32]

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.[33]

Specific Cancer Types

Breast Cancer

Colorectal Cancer

Non Small Cell Lung Cancer

Pancreatic Cancer

General Findings

Effects on the Immune System

Increased Vitality

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.[34]

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.[35] 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).[36]

A Phase 1, dose finding trial is being conducted on Iscador Pini in Israel. [37]

Pharmacologic Extraction

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.

Literature

  • Johnson, Steven; Winters, Nasha; Blanning, Adam; Debus, Marion; Faust, Paul; Hancock, Mark; Hinderberger, Peter (2022-02-25). Mistletoe and the Emerging Future of Integrative Oncology. SteinerBooks, Incorporated. ISBN 978-1-938685-33-0.
  • 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.

Weblinks

References

  1. ↑ Agrios, G. N. (2005). "Plant Pathology". PLANT DISEASES CAUSED BY PARASITIC HIGHER PLANTS, INVASIVE CLIMBING PLANTS, AND PARASITIC GREEN ALGAE. Elsevier. pp. 705–722. doi:10.1016/B978-0-08-047378-9.50019-1. ISBN 9780120445653.
  2. ↑ Alonso-Castro, A. J., Juárez-Vázquez, M. del C., Domínguez, F., González-Sánchez, I., Estrada-Castillón, E., López-Toledo, G., Chávez, M., Cerbón, M. A., García-Carranca, A. (1 August 2012). "The antitumoral effect of the American mistletoe Phoradendron serotinum (Raf.) M.C. Johnst. (Viscaceae) is associated with the release of immunity-related cytokines". Journal of Ethnopharmacology. 142 (3): 857–864. doi:10.1016/j.jep.2012.06.018. Retrieved 13 March 2023.
  3. ↑ van Emmichoven: Wer War Ita Wegman - Google Scholar, retrieved 13 March 2023
  4. ↑ Cummings, R. D., L. Schnaar, R. (2015). "Essentials of Glycobiology". In Varki, A., Cummings, R. D., Esko, J. D., Stanley, P., Hart, G. W., Aebi, M., Darvill, A. G., Kinoshita, T., Packer, N. H., Prestegard, J. H., Schnaar, R. L., Seeberger, P. H. (eds.). R-Type Lectins (3rd ed.). Cold Spring Harbor Laboratory Press.
  5. ↑ Vademecum of Anthroposophic Medicines. Best Practices for Mistletoe Use in Cancer Care. Verlag der Gesellschaft Anthroposophischer Arzte in Deutschland. 2019. ISBN 978-3-946951-06-3.
  6. ↑ Hajtó, T., Hostanska, K., Berki, T., Pálinkás, L., Boldizsár, F., Németh, P. (2005). "Oncopharmacological perspectives of a plant lectin (Viscum album agglutinin-I): overview of recent results from in vitro experiments and in vivo animal models, and their possible relevance for clinical applications". Evidence-Based Complementary and Alternative Medicine. 2 (1): 59–67.
  7. ↑ ((R, H.)), ((M, R.)), ((R, G.)), ((R, L.)), ((K, U.)), ((R, K.)) (Winter 2006). "Immunologic effects of mistletoe lectins: a placebo-controlled study in healthy subjects". Journal of the Society for Integrative Oncology. 4 (1). Retrieved 2 April 2023. Vancouver style error: non-Latin character in name 1 (help)
  8. ↑ Elluru, S., Duong Van Huyen, J.-P., Delignat, S., Prost, F., Bayry, J., Kazatchkine, M. D., Kaveri, S. V. (June 2006). "Molecular mechanisms underlying the immunomodulatory effects of mistletoe (Viscum album L.) extracts Iscador". Arzneimittel-Forschung. 56 (6A): 461–466. doi:10.1055/s-0031-1296813.
  9. ↑ Samuelsson, G., Pettersson, B. M. (1971). "The Amino Acid Sequence of Viscotoxin B from the European Mistletoe (Viscum album L, Loranthaceae)". European Journal of Biochemistry. 21 (1): 86–89. doi:10.1111/j.1432-1033.1971.tb01443.x. Retrieved 27 March 2023.
  10. ↑ Pal, A., Debreczeni, J. É., Sevvana, M., Gruene, T., Kahle, B., Zeeck, A., Sheldrick, G. M. (1 September 2008). "Structures of viscotoxins A1 and B2 from European mistletoe solved using native data alone". Acta Crystallographica Section D Biological Crystallography. 64 (9): 985–992. doi:10.1107/S0907444908022646. Retrieved 27 March 2023.
  11. ↑ Nawrot, R., Barylski, J., Nowicki, G., Broniarczyk, J., Buchwald, W., Goździcka-Józefiak, A. (2014). "Plant antimicrobial peptides". Folia Microbiologica. 59 (3): 181–196. doi:10.1007/s12223-013-0280-4. Retrieved 27 March 2023.
  12. ↑ Giudici, A. M., Regente, M. C., Villalaín, J., Pfüller, K., Pfüller, U., De La Canal, L. (2004). "Mistletoe viscotoxins induce membrane permeabilization and spore death in phytopathogenic fungi". Physiologia Plantarum. 121 (1): 2–7. doi:10.1111/j.0031-9317.2004.00259.x. Retrieved 27 March 2023.
  13. ↑ Mueller, E. A., Anderer, F. A. (1990). "A Viscum album oligosaccharide activating human natural cytotoxicity is an interferon gamma inducer". Cancer immunology, immunotherapy: CII. 32 (4): 221–227. doi:10.1007/BF01741704.
  14. ↑ Nazaruk, J., Orlikowski, P. (16 February 2016). "Phytochemical profile and therapeutic potential of Viscum album L." Natural Product Research. 30 (4): 373–385. doi:10.1080/14786419.2015.1022776. Retrieved 2 April 2023.
  15. ↑ Aa, F., ((A, T.)), ((G, T.)), ((A, T.)), ((A, B.)), ((G, K.)), ((S, A.)) (21 December 2022). "Multifunctional Roles of Betulinic Acid in Cancer Chemoprevention: Spotlight on JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and Non-Coding RNAs in the Inhibition of Carcinogenesis and Metastasis". Molecules (Basel, Switzerland). 28 (1). doi:10.3390/molecules28010067. Retrieved 2 April 2023.
  16. ↑ Paller, C. J., Wang, L., Fu, W., Kumar, R., Durham, J. N., Azad, N. S., Laheru, D. A., Browner, I., Kachhap, S. K., Boyapati, K., Odeny, T., Armstrong, D. K., Meyer, C. F., Gaillard, S., Brahmer, J. R., Page, I., Wang, H., Diaz, L. A., Jr. (28 February 2023). "Phase I Trial of Intravenous Mistletoe Extract in Advanced Cancer". Cancer Research Communications. 3 (2): 338–346. doi:10.1158/2767-9764.CRC-23-0002. Retrieved 13 March 2023.
  17. ↑ Huber, R., Schlodder, D., Effertz, C., Rieger, S., Tröger, W. (18 September 2017). "Safety of intravenously applied mistletoe extract – results from a phase I dose escalation study in patients with advanced cancer". BMC Complementary and Alternative Medicine. 17 (1): 465. doi:10.1186/s12906-017-1971-1. Retrieved 15 January 2023.
  18. ↑ Pelzer, F., Tröger, W. (1 September 2018). "Complementary Treatment with Mistletoe Extracts During Chemotherapy: Safety, Neutropenia, Fever, and Quality of Life Assessed in a Randomized Study". Journal of Alternative and Complementary Medicine. 24 (9–10): 954–961. doi:10.1089/acm.2018.0159. Retrieved 15 January 2023.
  19. ↑ Kienle, G. S., Grugel, R., Kiene, H. (28 August 2011). "Safety of higher dosages of Viscum album L. in animals and humans--systematic review of immune changes and safety parameters". BMC complementary and alternative medicine. 11: 72. doi:10.1186/1472-6882-11-72.
  20. ↑ Huber, R., Lüdtke, H., Wieber, J., Beckmann, C. (24 November 2011). "Safety and effects of two mistletoe preparations on production of Interleukin-6 and other immune parameters - a placebo controlled clinical trial in healthy subjects". BMC complementary and alternative medicine. 11: 116. doi:10.1186/1472-6882-11-116.
  21. ↑ Steele, M. L., Axtner, J., Happe, A., Kröz, M., Matthes, H., Schad, F. (2014). "Adverse Drug Reactions and Expected Effects to Therapy with Subcutaneous Mistletoe Extracts (Viscum album L.) in Cancer Patients". Evidence-Based Complementary and Alternative Medicine: eCAM. 2014: 724258. doi:10.1155/2014/724258.
  22. ↑ Steele, M. L., Axtner, J., Happe, A., Kröz, M., Matthes, H., Schad, F. (2014). "Safety of Intravenous Application of Mistletoe (Viscum album L.) Preparations in Oncology: An Observational Study". Evidence-Based Complementary and Alternative Medicine: eCAM. 2014: 236310. doi:10.1155/2014/236310.
  23. ↑ Thronicke, A., Oei, S. L., Merkle, A., Matthes, H., Schad, F. (6 September 2018). "Clinical Safety of Combined Targeted and Viscum album L. Therapy in Oncological Patients". Medicines. 5 (3): 100. doi:10.3390/medicines5030100. Retrieved 15 January 2023.
  24. ↑ Thronicke, A., Steele, M. L., Grah, C., Matthes, B., Schad, F. (13 December 2017). "Clinical safety of combined therapy of immune checkpoint inhibitors and Viscum album L. therapy in patients with advanced or metastatic cancer". BMC complementary and alternative medicine. 17 (1): 534. doi:10.1186/s12906-017-2045-0.
  25. ↑ Weissenstein, U., Kunz, M., Urech, K., Baumgartner, S. (8 January 2014). "Interaction of standardized mistletoe (Viscum album) extracts with chemotherapeutic drugs regarding cytostatic and cytotoxic effects in vitro". BMC Complementary and Alternative Medicine. 14 (1): 6. doi:10.1186/1472-6882-14-6. Retrieved 15 January 2023.
  26. ↑ Zuzak, T. J., Wasmuth, A., Bernitzki, S., Schwermer, M., Längler, A. (October 2018). "Safety of high-dose intravenous mistletoe therapy in pediatric cancer patients: A case series". Complementary Therapies in Medicine. 40: 198–202. doi:10.1016/j.ctim.2018.01.002.
  27. ↑ Oei, S. L., Thronicke, A., Kröz, M., Matthes, H., Schad, F. (26 February 2019). "Use and Safety of Viscum album L Applications in Cancer Patients With Preexisting Autoimmune Diseases: Findings From the Network Oncology Study". Integrative Cancer Therapies. 18: 1534735419832367. doi:10.1177/1534735419832367. Retrieved 15 January 2023.
  28. ↑ Steele, M. L., Axtner, J., Happe, A., Kröz, M., Matthes, H., Schad, F. (1 March 2015). "Use and Safety of Intratumoral Application of European Mistletoe (Viscum album L) Preparations in Oncology". Integrative Cancer Therapies. 14 (2): 140–148. doi:10.1177/1534735414563977. Retrieved 15 January 2023.
  29. ↑ 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. doi:10.1155/2012/219402. Retrieved 16 March 2023.
  30. ↑ Ernst, E., Schmidt, K., Steuer-Vogt, M. K. (1 November 2003). "Mistletoe for cancer? A systematic review of randomised clinical trials". International Journal of Cancer. 107 (2): 262–267. doi:10.1002/ijc.11386.
  31. ↑ Edzard Ernst, retrieved 17 March 2023 Text "Skeptical About Skeptics" ignored (help)
  32. ↑ Horneber, M., Ackeren, G., Linde, K., Rostock, M. (16 April 2008). "Mistletoe therapy in oncology". The Cochrane Database of Systematic Reviews. 2008 (2): CD003297. doi:10.1002/14651858.CD003297.pub2. Retrieved 17 March 2023.
  33. ↑ Kienle, G. S., Glockmann, A., Schink, M., Kiene, H. (11 June 2009). "Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research". Journal of Experimental & Clinical Cancer Research. 28 (1): 79. doi:10.1186/1756-9966-28-79. Retrieved 17 March 2023.
  34. ↑ https://clinicaltrials.gov/ct2/show/NCT02106572
  35. ↑ https://beta.clinicaltrials.gov/study/NCT05726383
  36. ↑ Longhi, A., Cesari, M., Serra, M., Mariani, E. (27 April 2020). "Long-Term Follow-up of a Randomized Study of Oral Etoposide versus Viscum album Fermentatum Pini as Maintenance Therapy in Osteosarcoma Patients in Complete Surgical Remission after Second Relapse". Sarcoma. 2020: e8260730. doi:10.1155/2020/8260730. Retrieved 15 March 2023.
  37. ↑ https://beta.clinicaltrials.gov/study/NCT04376931
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