Mistletoe (European)

• How It Works

  Mistletoe therapy may improve symptoms and quality of life for cancer patients, but definitive information is still lacking.

  Mistletoe is a semi-parasitic plant that grows on various host trees. Although some oral mistletoe products are sold as dietary supplements and homeopathic medicine, most scientific research has only evaluated intravenous or injected formulations that are not approved as prescription drugs in the United States.

  Basic research shows that mistletoe extracts may stimulate the immune system to fight cancer. Studies in humans show that mistletoe treatment may improve symptoms and reduce side effects of cancer treatments. A few studies indicate it may also have some effects on survival. More studies are needed to see if mistletoe can be used as supportive therapy in cancer care.

• Purported Uses
  • To treat cancer and cancer symptoms
    Laboratory and animal studies show some anticancer activity. Some human studies show that mistletoe extract can reduce symptoms from cancer treatments and that patients live longer. However, more studies are needed to confirm these effects.
  • To treat hepatitis
    Clinical trials show conflicting results.
  • To treat HIV and AIDS
    Some studies find that mistletoe extract can affect the immune system in HIV patients. However, there is not enough evidence to show that it can be used as a treatment.
  • To lower high blood pressure
    Laboratory data show that mistletoe may lower blood pressure, but no studies have been done to see if it is an effective treatment for high blood pressure.
  • As an immune stimulant
    Laboratory and animal studies as well as some human studies show that mistletoe can both modulate and stimulate the immune system.
• Do Not Take If
  • You are pregnant: Some mistletoe compounds can stimulate the uterus to contract, which can increase abortion risk.
  • You are taking cytochrome P450 3A4 substrate drugs: Mistletoe may increase the risk of side effects of these drugs.
• Side Effects

  Common: Fever, chills, elevated white blood cell count, reaction at injection site, hypersensitivity.

  Less common, may indicate toxicity: Diarrhea, vomiting, headache, low blood pressure, low heart rate, fainting or passing out, increased blood sugar, itching, rash.

  Most reactions were mild, but there are instances of severe toxicity and even death with self-administration or by ingesting raw mistletoe.

• Special Point

  Although orally administered mistletoe products are available, most clinical trials have evaluated the injectable forms of mistletoe, which are not approved for use in the United States by the Food and Drug Administration.

• Brand Name

  Helixor®, Iscador®, Iscador Qu®, Lektinol™, Cefalektin®, Eurixor®, ABNOBAviscum®, Abnoba-viscum Quercus

• Scientific Name

  Viscum album, Viscum coloratum

• Clinical Summary

  Mistletoe is a semi-parasitic plant that grows on various host trees. Mistletoe extracts are used for a variety of conditions including cancer, HIV, hepatitis, and degenerative joint disease. Oral preparations are available as dietary supplements and homeopathic remedies. However, most clinical research has evaluated mainly parenteral formulations, which are not approved for use in the United States by the Food and Drug Administration.

  Studies support the use of mistletoe to improve symptoms and quality of life, and reduce chemotherapy and radiotherapy side effects, including in pancreatic ^(13) (37), lung ⁽¹¹⁾, colorectal ⁽¹²⁾, and breast ⁽¹⁴⁾ cancers. Some studies suggest it may help prolong survival ^{(6) (8) (9) (13)}, but other study results are mixed ^{(17) (18) (19) (43)}. Preliminary studies suggest that intravesical mistletoe extract is safe and well tolerated in patients with nonmuscle invasive bladder cancer ⁽³⁸⁾, and that mistletoe extract injection may be efficacious for chemical pleurodesis in patients with malignant pleural effusion ^(39) (44).

  In two studies with 5-year follow-ups of breast cancer patients, mistletoe did not appear to negatively influence chemotherapy efficacy ⁽¹⁴⁾ and appeared to continue reductions in persistent symptoms ⁽¹⁵⁾. In patients with advanced solid tumors, the addition of mistletoe administration allowed for higher gemcitabine doses to be used without apparent pharmacokinetic interactions ⁽¹⁶⁾. Concomitant mistletoe appeared to reduce adverse events from monoclonal antibody therapy ⁽⁴⁵⁾ but not immune checkpoint inhibitors ⁽⁴⁶⁾. Benefits with mistletoe treatment in combination with medical care have also been reported ^(47) (48). Large prospective studies are needed to determine safety and whether these immune-related events translate to beneficial outcomes.

  Raw mistletoe contains toxic constituents. Possible adverse effects from mistletoe treatment include injection site reactions, chills, and fever ^{(16) (20) (39) (40) (41)}. Long-term use may also reduce T-cell function in cancer patients ⁽²¹⁾, but the majority of reactions were mild to moderate and dose-related ^(22) (49).

  Mistletoe inhibits CYP3A4 in vitro, so it could theoretically interact with drugs metabolized by this enzyme. However, in vitro studies show this effect only happens in very high doses and is unlikely when used in clinically relevant concentrations ^{(10) (23) (50)}.

• Purported Uses
  • Cancer symptom control
  • Cancer treatment
  • Hepatitis
  • HIV and AIDS
  • Hypertension
  • Immunostimulation
• Mechanism of Action

  In preclinical models, mistletoe has anti-inflammation ⁽¹⁾ and anticancer effects ^{(3) (4) (51)}. Mistletoe lectins are the most investigated single component of mistletoe extracts, with cytotoxic effects attributed in part to ribosome-inactivating properties and apoptotic induction ⁽⁵⁾. In vitro studies show that lectins induce macrophage cytotoxicity, stimulate immune-cell phagocytosis, increase TNFα, IL-1, IL-2, and IL-6 cytokine secretion, and enhance cytotoxicity ⁽²⁹⁾. In lymphoblastic leukemia cells, mistletoe extracts stimulate dendritic cell maturation and activation ⁽³⁰⁾ and induce dose-dependent apoptosis through caspase-8 and -9 dependent pathways ⁽²⁶⁾.

  In animal models, triterpene-containing mistletoe extracts produced the greatest apoptotic induction ⁽²⁶⁾ and improved efficacy against malignant melanoma compared with conventional extracts via reduced tumor angiogenesis ⁽³¹⁾. Viscotoxins may also be responsible for tumor-inhibiting and immune-stimulating activities ⁽²⁸⁾. However, mistletoe produced both pro- and anti-proliferative effects depending on dose ⁽³²⁾.

  Mistletoe preparations induce T-helper 2 immune response, as evidenced by significant eosinophilia during treatment in patients with chronic hepatitis C ⁽²⁾. Mistletoe-induced immune stimulation may explain physical improvements that contribute to increased quality of life in cancer patients ⁽⁵⁾.

• Contraindications

  Pregnant women should not consume mistletoe due to uterine stimulant activity of tyramine and unidentified constituents ⁽²⁷⁾.

• Adverse Reactions

  Common: Injection site reactions, fever ^{(39) (40) (52)}, flu-like symptoms ⁽⁴¹⁾, leukocytosis ^{(16) (20) (22)}.
  Uncommon: Diarrhea, nausea ⁽⁴⁰⁾, vomiting, headache, increased blood glucose, decreased blood pressure, syncope, generalized pruritus, urticaria ⁽²²⁾; bradycardia , organ toxicity ⁽³³⁾; fatigue, pain ^(39) (40).
  Long-term use: Reduced T-cell function in cancer patients ⁽²¹⁾.
  Most infusion reactions were mild to moderate and dose-related ^(22) (41).

  Case reports
  Subcutaneous inflammation mimicking metastatic malignancy: In a 61-year-old breast cancer patient 2 months post-surgery, induced by mistletoe injections self-administered over 12 months ⁽³⁵⁾.
  Fatalities: Rare, and due to excessive ingestion of mistletoe teas ⁽³³⁾.
  Severe hypertension: Possibly related to intratumoral injection in 1 patient ⁽⁴¹⁾.
  Hepatotoxicity: Significantly increased AST and ALT levels in a 55-year-old man with no significant medical history and a 10-day history of mild fever and brownish urine. Liver injury was related to the use of mistletoe and kudzu extracts. Values gradually returned to normal after 8 days of hospitalization ⁽⁴²⁾.

• Herb-Drug Interactions

  Cytochrome P450 3A4 substrates: Mistletoe inhibits CYP3A4 and may affect intracellular concentrations of drugs metabolized by this enzyme. However, the effect is minimal when used in clinically relevant concentrations ^{(10) (23) (50)}.

• References

  1. Shen JJ, Chiang MS, Kuo ML, et al. Partially purified extract and viscolin from Viscum coloratum attenuate airway inflammation and eosinophil infiltration in ovalbumin-sensitized mice. J Ethnopharmacol. Jun 1 2011;135(3):646-653.

  2. Huber R, Ludtke R, Klassen M, et al. Effects of a mistletoe preparation with defined lectin content on chronic hepatitis C: an individually controlled cohort study. Eur J Med Res. Sep 28 2001;6(9):399-405.

  3. Struh CM, Jager S, Schempp CM, et al. A novel triterpene extract from mistletoe induces rapid apoptosis in murine B16.F10 melanoma cells. Phytother Res. Oct 2012;26(10):1507-1512.

  4. Beuth J, Ko HL, Schneider H, et al. Intratumoral application of standardized mistletoe extracts down regulates tumor weight via decreased cell proliferation, increased apoptosis and necrosis in a murine model. Anticancer Res. Nov-Dec 2006;26(6B):4451-4456.

  5. Melzer J, Iten F, Hostanska K, et al. Efficacy and safety of mistletoe preparations (Viscum album) for patients with cancer diseases. A systematic review. Forsch Komplementmed. Aug 2009;16(4):217-226.

  6. Ostermann T, Raak C, Bussing A. Survival of cancer patients treated with mistletoe extract (Iscador): a systematic literature review. BMC Cancer. 2009;9:451.

  7. Horneber MA, Bueschel G, Huber R, et al. Mistletoe therapy in oncology. Cochrane Database Syst Rev. 2008(2):CD003297. doi: 10.1002/14651858.CD003297.pub2

  8. Grossarth-Maticek R, Kiene H, Baumgartner SM, et al. Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Altern Ther Health Med. May-Jun 2001;7(3):57-66, 68-72, 74-56 passim.

  9. Grossarth-Maticek R, Ziegler R. Randomised and non-randomised prospective controlled cohort studies in matched-pair design for the long-term therapy of breast cancer patients with a mistletoe preparation (Iscador): a re-analysis. Eur J Med Res. Nov 30 2006;11(11):485-495.

  10. Weissenstein U, Kunz M, Urech K, et al. Interaction of standardized mistletoe (Viscum album) extracts with chemotherapeutic drugs regarding cytostatic and cytotoxic effects in vitro. BMC Complement Altern Med. 2014;14:6.

  11. Bar-Sela G, Wollner M, Hammer L, et al. Mistletoe as complementary treatment in patients with advanced non-small-cell lung cancer treated with carboplatin-based combinations: a randomised phase II study. Eur J Cancer. Mar 2013;49(5):1058-1064.

  12. Friedel WE, Matthes H, Bock PR, et al. Systematic evaluation of the clinical effects of supportive mistletoe treatment within chemo- and/or radiotherapy protocols and long-term mistletoe application in nonmetastatic colorectal carcinoma: multicenter, controlled, observational cohort study. J Soc Integr Oncol. Fall 2009;7(4):137-145.

  13. Troger W, Galun D, Reif M, et al. Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: a randomised clinical trial on overall survival. Eur J Cancer. Dec 2013;49(18):3788-3797.

  14. Troger W, Zdrale Z, Stankovic N, et al. Five-year follow-up of patients with early stage breast cancer after a randomized study comparing additional treatment with Viscum album (L.) extract to chemotherapy alone. Breast Cancer (Auckl). 2012;6:173-180.

  15. Beuth J, Schneider B, Schierholz JM. Impact of complementary treatment of breast cancer patients with standardized mistletoe extract during aftercare: a controlled multicenter comparative epidemiological cohort study. Anticancer Res. Jan-Feb 2008;28(1b):523-527.

  16. Mansky PJ, Wallerstedt DB, Sannes TS, et al. NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors. Evid Based Complement Alternat Med. 2013;2013:964592.

  17. Bar-Sela G, Haim N. Abnoba-viscum (mistletoe extract) in metastatic colorectal carcinoma resistant to 5-fluorouracil and leucovorin-based chemotherapy. Med Oncol. 2004;21(3):251-254.

  18. Kleeberg UR, Suciu S, Brocker EB, et al. Final results of the EORTC 18871/DKG 80-1 randomised phase III trial. rIFN-alpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis. Eur J Cancer. Feb 2004;40(3):390-402.

  19. Steuer-Vogt MK, Bonkowsky V, Ambrosch P, et al. The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial. Eur J Cancer. Jan 2001;37(1):23-31.

  20. Huber R, Eisenbraun J, Miletzki B, et al. Pharmacokinetics of natural mistletoe lectins after subcutaneous injection. Eur J Clin Pharmacol. Sep 2010;66(9):889-897.

  21. Bussing A, Stumpf C, Troger W, et al. Course of mitogen-stimulated T lymphocytes in cancer patients treated with Viscum album extracts. Anticancer Res. Jul-Aug 2007;27(4C):2903-2910.

  22. Steele ML, Axtner J, Happe A, et al. Adverse Drug Reactions and Expected Effects to Therapy with Subcutaneous Mistletoe Extracts (Viscum album L.) in Cancer Patients. Evid Based Complement Alternat Med. 2014;2014:724258.

  23. Engdal S, Nilsen OG. In vitro inhibition of CYP3A4 by herbal remedies frequently used by cancer patients. Phytother Res. Jul 2009;23(7):906-912.

  24. Bar-Sela G. White-berry mistletoe (Viscum album L.) as complementary treatment in cancer: Does it help? Eur J Integr Med. 2011;3:e55-e62.

  25. de Giorgio A, Stebbing J. Mistletoe: for cancer or just for Christmas? Lancet Oncol. Dec 2013;14(13):1264-1265.

  26. Delebinski CI, Jaeger S, Kemnitz-Hassanin K, et al. A new development of triterpene acid-containing extracts from Viscum album L. displays synergistic induction of apoptosis in acute lymphoblastic leukaemia. Cell Prolif. Apr 2012;45(2):176-187.

  27. Ernst E. Herbal medicinal products during pregnancy: are they safe? BJOG. Mar 2002;109(3):227-235.

  28. Kleijnen J, Knipschild P. Mistletoe treatment for cancer review of controlled trials in humans. Phytomedicine. Dec 1994;1(3):255-260.

  29. Goebell PJ, Otto T, Suhr J, et al. Evaluation of an unconventional treatment modality with mistletoe lectin to prevent recurrence of superficial bladder cancer: a randomized phase II trial. J Urol. Jul 2002;168(1):72-75.

  30. Elluru SR, Duong van Huyen JP, Delignat S, et al. Induction of maturation and activation of human dendritic cells: a mechanism underlying the beneficial effect of Viscum album as complimentary therapy in cancer. BMC Cancer. 2008;8:161.

  31. Struh CM, Jager S, Kersten A, et al. Triterpenoids amplify anti-tumoral effects of mistletoe extracts on murine B16.f10 melanoma in vivo. PLoS One. 2013;8(4):e62168.

  32. Lyu SY, Park WB. Effects of Korean mistletoe lectin (Viscum album coloratum) on proliferation and cytokine expression in human peripheral blood mononuclear cells and T-lymphocytes. Arch Pharm Res. Oct 2007;30(10):1252-1264.

  33. Evens ZN, Stellpflug SJ. Holiday plants with toxic misconceptions. West J Emerg Med. Dec 2012;13(6):538-542.

  34. Rosell S, Samuelsson G. Effect of mistletoe viscotoxin and phoratoxin on blood circulation. Toxicon. Aug 1966;4(2):107-110.

  35. Finall AI, McIntosh SA, Thompson WD. Subcutaneous inflammation mimicking metastatic malignancy induced by injection of mistletoe extract. BMJ. Dec 23 2006;333(7582):1293-1294.

  36. Hall AH, Spoerke DG, Rumack BH. Assessing mistletoe toxicity. Ann Emerg Med. Nov 1986;15(11):1320-1323.

  37. Troger W, Galun D, Reif M, et al. Quality of life of patients with advanced pancreatic cancer during treatment with mistletoe: a randomized controlled trial. Dtsch Arztebl Int. Jul 21 2014;111(29-30):493-502, 433 p following 502.

  38. Rose A, El-Leithy T, vom Dorp F, et al. Mistletoe Plant Extract in Patients with Nonmuscle Invasive Bladder Cancer: Results of a Phase Ib/IIa Single Group Dose Escalation Study. J Urol. Oct 2015;194(4):939-943.

  39. Cho JS, Na KJ, Lee Y, et al. Chemical Pleurodesis Using Mistletoe Extraction (ABNOVAviscum((R)) Injection) for Malignant Pleural Effusion. Ann Thorac Cardiovasc Surg. 2016;22(1):20-26.

  40. Schad F, Atxner J, Buchwald D, et al. Intratumoral Mistletoe (Viscum album L) Therapy in Patients With Unresectable Pancreas Carcinoma: A Retrospective Analysis. Integr Cancer Ther. Jul 2014;13(4):332-340.

  41. Steele ML, Axtner J, Happe A, et al. Use and safety of intratumoral application of European mistletoe (Viscum album L) preparations in Oncology. Integr Cancer Ther. Mar 2015;14(2):140-148.

  42. Kim HJ, Kim H, Ahn JH, et al. Liver injury induced by herbal extracts containing mistletoe and kudzu. J Altern Complement Med. Mar 2015;21(3):180-185.

  43. Fritz P, Dippon J, Muller S, et al. Is Mistletoe Treatment Beneficial in Invasive Breast Cancer? A New Approach to an Unresolved Problem. Anticancer Res. Mar 2018;38(3):1585-1593.

  44. Eom JS, Ahn HY, Mok JH, et al. Pleurodesis Using Mistletoe Extract Delivered via a Spray Catheter during Semirigid Pleuroscopy for Managing Symptomatic Malignant Pleural Effusion. Respiration. 2018;95(3):177-181.

  45. Schad F, Axtner J, Kroz M, et al. Safety of Combined Treatment With Monoclonal Antibodies and Viscum album L Preparations. Integr Cancer Ther. Mar 2018;17(1):41-51.

  46. Thronicke A, Steele ML, Grah C, et al. Clinical safety of combined therapy of immune checkpoint inhibitors and Viscum album L. therapy in patients with advanced or metastatic cancer. BMC Complement Altern Med. Dec 13 2017;17(1):534.

  47. Werthmann PG, Huber R, Kienle GS. Durable clinical remission of a skull metastasis under intralesional Viscum album extract therapy: Case report. Head Neck. Jul 2018;40(7):E77-e81.

  48. Werthmann PG, Kindermann L, Kienle GS. A 21-year course of Merkel cell carcinoma with adjuvant Viscum album extract treatment: A case report. Complement Ther Med. Jun 2018;38:58-60.

  49. Schad F, Thronicke A, Merkle A, et al. Immune-related and adverse drug reactions to low versus high initial doses of Viscum album L. in cancer patients. Phytomedicine. Dec 1 2017;36:54-58.

  50. Schink M, Dehus O. Effects of mistletoe products on pharmacokinetic drug turnover by inhibition and induction of cytochrome P450 activities. BMC Complement Altern Med. Dec 4 2017;17(1):521.

  51. Kim S, Kim KC, Lee C. Mistletoe (Viscum album) extract targets Axl to suppress cell proliferation and overcome cisplatin- and erlotinib-resistance in non-small cell lung cancer cells. Phytomedicine. Dec 1 2017;36:183-193.

  52. Schlappi M, Ewald C, Kuehn JJ, et al. Fever Therapy With Intravenously Applied Mistletoe Extracts for Cancer Patients: A Retrospective Study. Integr Cancer Ther. Dec 2017;16(4):479-484.