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Mistletoe

Scientific Name(s): Phoradendron tomentosum (DC.) Engelm. ex A. Gray (Christmas mistletoe), Viscum album L. (European mistletoe)
Common Name(s): All heal, Bird lime, Devil's fuge, Golden bough, Iscador, Mistel, Mistletoe

Medically reviewed by Drugs.com. Last updated on Sep 24, 2018.

Clinical Overview

Use

Mistletoe has been used to treat cancer, although there is a lack of quality clinical trials and little evidence of an effect. Further study is needed. In folk medicine, it has been used for its cardiovascular properties. Clinical efficacy has not been established. Injectable mistletoe extract is widely used in Europe but is not licensed for use in the United States.

Dosing

Crude mistletoe fruit or herb is used to make a tea to treat hypertension at a dosage of 10 g/day. There are a number of proprietary extracts containing low levels of mistletoe lectin-Ι (ML-Ι) used as adjuvant cancer therapies. These extracts usually are given by intravenous (IV) or subcutaneous injection at dosages of 0.01 to 30 mg several times per week. Mistletoe preparations, produced according to anthroposophical methods, are given in incrementally increasing dosages depending on the patient's general condition and response to the injection. Use in pediatric patients has been reported. The pharmacokinetics in healthy adults has been determined.

Contraindications

Data are limited. Use of mistletoe extracts in patients with primary or secondary brain tumors, leukemia, or malignant lymphoma is contraindicated.

Pregnancy/Lactation

Mistletoe contains toxic constituents. Avoid use during pregnancy or lactation.

Interactions

None well documented.

Adverse Reactions

Local reactions following injection include redness, itching, inflammation, and induration at the injection site. Systemic reactions include mild fever or flu-like symptoms. Anaphylaxis has been reported.

Toxicology

Poison centers report toxicity of the whole plant, but especially mistletoe berries. The use of preparations standardized to small doses of ML-Ι or depleted of lectins may reduce toxicity.

Botany

The family Viscaceae (Christmas Mistletoe family) contains 5 genera and more than 50 different mistletoe species. Synonyms include Phoradendron flavescens, Phoradendron serotinum, and Viscum coloratum. Mistletoe is a hemiparasitic plant that grows on a wide variety of host trees such as pine, oak, birch, and apple. The term hemiparasitic indicates that the mistletoe plant carries out photosynthesis independently but obtains its water and minerals from the host. There are several subspecies and varieties of mistletoe, which are defined by the host that they parasitize. European mistletoe is dioecious, with male and female flowers on separate plants. They are pollinated by insects and bear small white berries on evergreen foliage. Other varieties bear red berries.1, 2

History

Mistletoe preparations have been used medicinally in Europe for centuries to treat epilepsy, infertility, hypertension, and arthritis. The Celtic priests, known as Druids, revered the oak tree and the mistletoe that grew upon it, according to Roman author and naturalist Gaius Plinius Secundus (also known as Pliny the Elder). At the winter celebration of Samhain, the sacred oaks were bare except for the green boughs of mistletoe. This was taken as a sign of eternal fertility. The Celts placed a sprig of mistletoe above the door of their houses. Its sacred nature prohibited fighting beneath it. This evolved over centuries into the custom of kissing underneath mistletoe at Christmas.3 In 1921, the Austrian anthroposophical spiritual leader Rudolf Steiner suggested that mistletoe might be used to treat cancer, based on the observation that mistletoe, like cancer, is parasitic and lethal to its host.4 Swiss and German clinics were founded to implement this idea and are still actively using a mistletoe preparation fermented with a strain of Lactobacillus for 3 days, a process that is more aligned to alchemy and homeopathy than pharmacology.4, 5

Chemistry

The most distinctive constituents of V. album are its proteins, which are of 2 types: the viscotoxins, which are small (5 kDa), cystine-rich basic proteins (known as thionins), and the larger mistletoe lectins. Four viscotoxins (A1, A2, A3, and B) have been isolated and sequenced.6 They are highly homologous 46–amino acid proteins, differing from one another at a few positions. The 3-dimensional structure of viscotoxin A3 has been elucidated by nuclear magnetic resonance methods.7 The viscotoxin profile of the 3 European subspecies of V. album has been determined.8 Two novel viscotoxins, termed 1-PS and U-PS, were found in subspecies austriacum (pine) and subspecies abietis (fir). The viscotoxin profile of subspecies album did not vary appreciably with 7 different hosts. The American species P. tomentosum yielded a homolog known as phoratoxin.2 The preparation Iscador has been shown to contain similar amounts of viscotoxins compared with the unfermented V. album extract.9

Lectins

Viscumin, a toxic lectin, was isolated from V. album and shown to be a type ΙΙ ribosome-inactivating protein.10 Three distinct lectins (ML-Ι [viscumin], ML-ΙΙ, and ML-ΙΙΙ) were isolated by another group and shown to have different carbohydrate-binding specificities.11, 12 The complete amino acid sequence of ML-Ι B-chain has been obtained, showing homology to other galactose-specific lectins, such as ricin and abrin.13 The X-ray diffraction 3-dimensional structure of ML-Ι has been obtained in the free state14 and bound to beta-galactose.15 ML-Ι binds to several sialylglycoproteins in addition to the galactose-binding specificity initially identified.16, 17 The structural features important for carbohydrate recognition have been described in detail.18, 19 A minor chitin-binding lectin completely distinct from ML-Ι-ΙΙΙ was isolated.20 Examination of the commercial preparation Iscador has shown that ML-Ι is modified or degraded, while ML-ΙΙ and ML-ΙΙΙ are still present.5, 10, 21

Carbohydrates

The water-soluble polysaccharides of V. album and Iscador have been purified and characterized. A highly esterified galactouronan and a complex arabinogalactan were identified, with the corresponding polysaccharides from Iscador having lower molecular weights compared with those of the native, unfermented extract.22

Small molecular weight compounds

The phenylpropanoids syringin, syringenin-apiosylglucoside, and eleutheroside E have been found in V. album, and have been used to identify and standardize mistletoe preparations.10, 23 The syringin content of mistletoe growing on different host plants has been measured.24 A number of known and novel chalcone and flavanone glycosides have been reported from European V. album.25, 26 Inositol derivatives are widespread in the Viscaceae family and occur at relatively high concentrations in all species of mistletoe. They are thought to play a role in osmotic balance.27 Other miscellaneous compounds have been reported.28, 29 A report of alkaloids in the plant has not been substantiated by isolation in pure form or structure elucidation.30

Uses and Pharmacology

Because of the potential toxicity of mistletoe, many studies have been done in vitro. Methodology of clinical trials is generally poor.

Cancer

Despite a plethora of experiments to determine a mechanism of action for mistletoe, no clear pathway has been identified. Proposed mechanisms generally focus on direct cytotoxic action (apoptosis induction) or immunomodulation (eg, enhanced natural killer cell activity, increased production of interleukins and tumor necrosis factor-alpha, activation of mononuclear cells, stimulation of granulocyte phagocytosis).40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 Therapeutic activity is considered to be caused by mistletoe lectins65; however, other cytotoxic compounds may contribute.66

Clinical data

Several systematic reviews of clinical trials have been published.65, 67, 68, 69, 70, 71 Outcome measures include survival times, tumor response, quality of life, psychological distress, adverse reactions, and safety.65 All reviews note the poor methodology in many of the trials; the diversity of extracts (different species, different extraction methods, and different host trees) and the use of various treatment regimens make systematic analysis difficult. No evidence of effect can be shown. A positive and negative trend were found for trials included in the reviews.65, 67, 68 Two quality trials of mistletoe as adjuvant to chemotherapy in breast cancer showed positive effect (quality of life, reduction of adverse reactions of chemotherapy), and 4 trials (including head and neck cancer and melanoma) with good methodology showed evidence of no effect on increased survival.65 A randomized, open, phase 3 trial was conducted in Serbian adults with inoperable advanced local or metastatic pancreatic cancer. Data analyzed from 168 survivors found statistically and clinically significant improvement in quality of life parameters with administration of subcutaneous mistletoe 3 times weekly for up to 1 year compared with those receiving only best supportive care. Mistletoe extract was initiated at 0.01 mg and titrated up to a target dose of 10 mg per injection.95 Reviewers considered it desirable to enroll patients in further clinical trials.65, 67, 71 Injectable mistletoe is not approved as a cancer treatment in the United States.71 Some in vitro and in vivo experiments and clinical studies suggest that interleukins can stimulate proliferation of certain cancer cells, and hence mistletoe therapy may not be without risk in cancer patients.67 Use of mistletoe extracts in patients with primary or secondary brain tumors, leukemia, or malignant lymphoma is contraindicated.67

Cardiovascular

In European folk medicine, a primary use of mistletoe is for its cardiovascular properties. However, clinical trials to support this use are lacking. Viscotoxins have been shown to induce reflex bradycardia and possess negative inotropic effects in the isolated animal cardiac muscle, as well as vasoconstriction at higher doses.72, 73 Phoratoxin demonstrates action on skeletal muscle fibers.74 Phenylpropanoids might also play a role in mistletoe's cardiovascular effects through a postulated inhibition of cyclic adenosine monophosphate phosphodiesterase.75, 76

Dosing

Crude mistletoe fruit or herb is used to make a tea for hypertension at a dosage of 10 g/day.

Iscador, a proprietary fermented product with different properties to unfermented mistletoe extracts, contains low levels of ML-Ι (10 mg extract contains 750 ng lectin).63Iscador extract usually is given by IV or subcutaneous injection at dosages of 0.1 to 30 mg several times per week.77, 78, 79, 80 Mistletoe preparations produced according to anthroposophical methods are given in incrementally increasing dosages depending on the patient's general condition and response to the injection.65 Therapy for solid tumors has used mistletoe preparations containing lectin 20,000 ng/mL or viscotoxins 100 mcg/mL by either the intratumoral, subcutaneous, or IV route. Iscador has not been approved for use in the United States.81

Use in pediatric patients has been reported.82 The pharmacokinetics in healthy adults has been determined.83 Peak plasma concentrations were obtained 1 to 2 hours after subcutaneous injection, and mistletoe preparation was still detectable in some of the volunteers after 2 weeks.83 An enteric-coated mistletoe-alginate/chitosan complex has been developed to overcome the poor bioavailability of oral mistletoe.84

Pregnancy / Lactation

Mistletoe contains toxic constituents. Avoid use during pregnancy or lactation.85, 86

Interactions

None well documented.

Adverse Reactions

Clinical trials on adverse reactions related to mistletoe administration ranged from a few reactions to as many as 45% of trial participants experiencing some adverse reaction.65, 67 The majority of adverse reactions have been mild to moderate, dose-related, and did not require treatment.94 Local reactions following injection include redness, itching, and induration at the injection site, lymphadenopathy, and increased body temperature.94 Subcutaneous inflammation following injection of the extract has been reported87 and this has been noted as a potential methodological flaw for blinding in future trials.88 Systemic reactions are less common and include blood glucose changes, blood pressure changes, syncope, rash, urticarial, mild fever, or flu-like symptoms.65, 94

Toxicology

Mistletoe is considered to be a toxic plant, and its content of toxic lectins lends support to this.89 Poison centers report toxicity of the whole plant, but especially the berries. Mild gastroenteritis, seizures, hallucinations, and anaphylaxis have been reported.70, 90, 91, 92, 93 Use of preparations standardized to small doses of ML-Ι (1 ng/injection) or depleted lectins by fermentation may reduce toxicity.9

Index Terms

  • Phoradendron flavescens
  • Phoradendron serotinum
  • Viscum coloratum

References

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