Mistletoe (European)

Health Care Professional Information

Scientific Name
Viscum album, Viscum coloratum
Common Name

Viscum, all-heal, birdlime, white-berry mistletoe, European mistletoe

Brand Name

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

Clinical Summary

Mistletoe is a semi-parasitic plant that grows on various host trees. Extracts of this plant 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, research reported in the literature has only evaluated parenterally administered formulations thus far, which are not approved for use in the United States by the Food and Drug Administration.

In animal models, mistletoe injections attenuated airway inflammation and eosinophil infiltration (1). An injectable form of mistletoe lectins reduced frequency and intensity of clinical signs and symptoms of hepatitis C (2), although little has been added to the literature since this earlier study. There are no published trials evaluating mistletoe for HIV or arthritis.

Mistletoe extracts have been noted to have anticancer effects in animal models (3) (4). Earlier studies in humans support the use of mistletoe for cancer supportive care to improve symptoms, reduce chemotherapy and radiotherapy side effects, and prolong survival (5) (6) (7). Epidemiologic data also suggest a survival advantage following mistletoe treatment (8) (9).

In more recent studies, simultaneous exposure of various cancer cell lines to mistletoe extract along with doxorubicin, gemcitabine, docetaxel, or cisplatin does not appear to inhibit chemotherapy and may produce additive effects (10). In human studies, mistletoe improved cancer-treatment related toxicities in patients with advanced non-small cell lung cancer (11) and colorectal cancer (12), and reduced symptoms and improved quality of life (QoL) in patients with pancreatic (13) and breast (14) cancers. 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). Mistletoe administered in conjunction with gemcitabine in patients with advanced solid tumors allowed higher gemcitabine doses to be used without apparent effects from mistletoe on gemcitabine pharmacokinetics (16). Although mistletoe appeared to prolong survival in patients with locally advanced or metastatic pancreatic cancer (13), no significant survival effects were found in older studies for patients with metastatic colorectal cancer (17), melanoma (18), or head and neck cancer (19).

Raw mistletoe contains toxic constituents. Possible adverse effects from mistletoe treatment include injection site reactions, chills, and fever (16) (20). Long-term use may also reduce T-cell function in cancer patients (21), but the majority of adverse reactions were mild to moderate and dose-related (22). Because mistletoe inhibits CYP3A4 in vitro, it could theoretically interact with drugs metabolized by this enzyme (23).

Purported Uses
  • Arthritis
  • Cancer symptom control
  • Cancer treatment
  • Hepatitis
  • HIV and AIDS
  • Hypertension
  • Immunostimulation
Constituents
  • Glycoproteins: Lectins I, II, and III
  • Polypeptides: Viscotoxins A2, A3, and B
  • Triterpene acids
  • Flavonoids
  • Amines: tyramine
  • Amino acids, oligo- and poly-saccharides, membrane lipids
    (24) (25) (26) (27) (28)
Mechanism of Action

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). Lectins induce macrophage cytotoxicity, stimulate phagocytosis of immune cells, increase TNFα, IL-1, IL-2, and IL-6 cytokine secretion, and enhance cytotoxicity effects on various cell lines in vitro (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 induction of apoptosis (26) and appeared to improve efficacy against malignant melanoma compared with conventional mistletoe extracts via reduced tumor angiogenesis (31). Viscotoxins from mistletoe are also thought to be responsible for immunostimulant and tumor-inhibiting activities (28). However, mistletoe has been shown to produce 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 the physical improvements that contribute to reported improvements in cancer patient QoL (5), although others counter that there is no clear mechanistic explanation as to why non-specific immune activation should enhance antitumor activity, even as increased neutrophil counts are held to be a satisfactory endpoint (25).

Pharmacokinetics

Individual serum concentrations of natural mistletoe lectins from a commercially available mistletoe preparation injected in healthy volunteers varied widely, with mean and median peak concentrations at 1 and 2 h post-injection respectively, and some subjects with detectable concentrations 2 weeks thereafter (20).

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, flu-like symptoms, leukocytosis (16) (20) (22)
Uncommon: Diarrhea, nausea, vomiting, headache, increased blood glucose, decreased blood pressure, syncope, generalized pruritus, urticaria (22); bradycardia , organ toxicity (33)
Long-term use: Reduced T-cell function in cancer patients (21)
Other: In animal models, hypotension and bradycardia with crude extracts (34)

The majority of adverse reactions to infusions were mild to moderate, dose-related, and did not require treatment in a large multicenter, observational study of cancer patients (22).

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) (36).

Herb-Drug Interactions

Cytochrome P450 3A4 substrates: Mistletoe inhibits CYP3A4 and may therefore affect the intracellular concentration of drugs metabolized by this enzyme, although clinically relevant systemic or intestinal interactions with CYP3A4 were considered unlikely (23).

Literature Summary and Critique

Troger W, 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. 2013;49:3788-3797. doi: 10.1016/j.ejca.2013.06.043
In this prospective, open-label phase III study, patients with advanced or metastatic pancreatic cancer were randomized to subcutaneous mistletoe injections or no additional treatment along with best supportive care (BSC) for both groups. A dose-escalation (0.01–10 mg), thrice-weekly administration schedule was used for mistletoe injections. Group-sequential analyses was pre-planned to occur after 220, 320 and 428 patients met off-study criteria. Participants were stratified into predefined good- or poor-prognosis groups. Overall survival (OS) at 12 months was assessed as the primary endpoint. At interim analysis (n=220), median OS was significantly longer for mistletoe compared with BSC-only patients (4.8 vs 2.7 months respectively; prognosis-adjusted hazard ratio, HR=0.49; P<.0001). When evaluated by subgroups, good-prognosis median OS was 6.6 versus 3.2 months (HR=0.43; P<.0001), and poor-prognosis median OS was 3.4 versus 2.0 months respectively (HR=0.55; P=0.0031). Frequency and severity of symptoms that included pain (96.9%), loss of energy (70.9%), weight loss (42.5%), nausea/emesis (18.9%), diarrhea (2.4%), and anxiety (2.4%) were significantly lower for intervention-group patients (P<.0001 for each parameter except diarrhea [P=.0033] and anxiety [P=.046]). No mistletoe-related adverse events were observed. The study indicates thus far that mistletoe may prolong survival in some pancreatic cancer patients and reduce disease-related symptoms. Secondary endpoint results that include QOL and concomitant medications will be published separately.

Bar-Sela G, 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. 2013;49:1058-1064. doi: 10.1016/j.ejca.2012.11.007
A total of 72 patients with advanced non-small cell lung cancer were randomized to receive mistletoe extract with first-line carboplatin-based chemotherapy (n=33) or chemotherapy alone (CT; n=39) thrice weekly until tumor progression to evaluate any benefits on treatment-related side-effects and QoL. A majority of patients had Stage IV disease (65%) and squamous histology (62%). There were no differences in median OS between groups. More control patients had CT dose reductions (44% vs 13%, P=.005), Grade 3/4 non-hematological toxicities (41% vs 16%, P =.043), and hospitalizations (54% vs 24%, P=.016). Although the addition of mistletoe therapy did not improve total adverse events or QoL, the benefits to other treatment-related toxicities warrants further study.

Dosage (Inside MSKCC Only)
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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. doi: 10.1016/j.jep.2011.03.065
  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. doi: 10.1002/ptr.4604
  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. doi: 10.1159/000226249
  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. doi: 10.1186/1471-2407-9-451
  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. doi: 10.1186/1472-6882-14-6
  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. doi: 10.1016/j.ejca.2012.11.007
  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. doi: 10.1016/j.ejca.2013.06.043
  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. doi: 10.4137/bcbcr.s10558
  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. doi: 10.1155/2013/964592
  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. doi: 10.1385/MO:21:3:251
  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. doi: 10.1007/s00228-010-0830-5
  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. doi: 10.1155/2014/724258
  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. doi: 10.1002/ptr.2750
  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. doi: 10.1016/s1470-2045(13)70560-6
  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. doi: 10.1111/j.1365-2184.2011.00801.x
  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. doi: 10.1016/S0944-7113(11)80073-5
  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. doi: 10.1186/1471-2407-8-161
  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. doi: 10.1371/journal.pone.0062168
  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. doi: 10.5811/westjem.2012.8.12572
  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. doi: 10.1136/bmj.39044.460023.BE
  36. Hall AH, Spoerke DG, Rumack BH. Assessing mistletoe toxicity. Ann Emerg Med. Nov 1986;15(11):1320-1323.

Consumer Information

How It Works

Bottom Line: Mistletoe therapy may improve symptoms and quality of life for cancer patients, but definitive information on these benefits 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, scientific research has only evaluated intravenous or injected formulations that are not approved as prescription drugs in the United States. Laboratory research shows that mistletoe extracts are able to stimulate the activity of several cells and factors of the immune system. In addition, animal studies show that mistletoe extracts can have anti-tumor activity. Studies in humans show that mistletoe treatment may improve symptoms as well as the ability to tolerate cancer treatments, but most studies on survival improvements do not show significant effects. More rigorous studies are needed to determine whether mistletoe can be considered an effective supportive therapy in cancer care.

Purported Uses
  • To treat arthritis
    There are no data to substantiate this claim.
  • To treat cancer and cancer symptoms
    Laboratory and animal studies show some anti-cancer activity, but clinical trials have not been able to confirm the same effect in humans. Studies with cancer patients appear to support that mistletoe can improve symptoms and quality of life.
  • To treat hepatitis
    Clinical trials show conflicting results.
  • To treat HIV and AIDS
    No scientific evidence supports this use.
  • To lower high blood pressure
    Laboratory data show that mistletoe may lower blood pressure, but no studies have been done to see whether this could translate into a 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.
Research Evidence

To treat cancer
A few studies on mistletoe therapy for colorectal, melanoma, and head and neck cancer patients have not shown survival benefit. However one study in patients with advanced pancreatic cancer did see both survival and symptom improvements. A few studies have also shown that chemotherapy regimens appear to be better tolerated and not negatively affected when adding a prescribed mistletoe regimen. More studies are needed to confirm these effects.

Do Not Take If
  • You are pregnant: Some mistletoe compounds can stimulate the uterus to contract, which can increase abortion risk.
  • You are taking drugs that are substrates of Cytochrome P450 3A4: 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 to infusions under medical care were mild to moderate. Rare instances of severe toxicity, reactions, or even death have occurred with self-administration or by ingesting other forms of mistletoe.
Special Point

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

E-mail your questions and comments to aboutherbs@mskcc.org.