Mistletoe
Scientific Name(s): Phoradendron tomentosum (DC.) Engelm. ex A. Gray (Christmas mistletoe), Viscum album L. (European mistletoe), Viscum album L. var. coloratum (Kom.) Ohwi (Korean mistletoe), Viscum capense L. (South African mistletoe)
Common Name(s): All heal, Bird lime, Devil's fuge, Ghwar, Golden bough, Guch, Mistel, Mistletoe
Medically reviewed by Drugs.com. Last updated on Nov 30, 2022.
Clinical Overview
Use
Clinical efficacy has not been established for use of mistletoe in any condition.
Dosing
Clinical data are lacking to provide dosing recommendations for mistletoe for any indication.
Contraindications
Data are limited. Use of mistletoe extracts in individuals with primary or secondary brain tumors, leukemia, or malignant lymphoma is contraindicated.
Pregnancy/Lactation
Avoid use. Mistletoe contains toxic constituents.
Interactions
A false-positive test for nodal involvement has been reported with use of homeopathic mistletoe in a patient with Hodgkin lymphoma. Herbs (hypotensive properties) may enhance the hypotensive effect of blood pressure–lowering agents. Herbs (hypotensive properties) may enhance the adverse/toxic effect of other herbs (hypotensive properties). Excessive blood pressure lowering may manifest.
Adverse Reactions
Little to no data are available regarding adverse effects related to commercial mistletoe supplements. Up to 45% of clinical trial participants have experienced adverse reactions associated with prescription injectable mistletoe dosage forms, which are not available or approved for use in the United States.
Toxicology
Poison control centers report toxicity of the whole plant, but especially mistletoe berries. Use of preparations standardized to small doses of mistletoe lectin I (ML-Ι) or depleted of lectins may reduce toxicity.
Scientific Family
- Viscaceae
Botany
The family Viscaceae (Christmas mistletoe family) contains 5 genera and more than 50 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.(Becker 1986, USDA 2020)
History
Mistletoe preparations have been used medicinally in Europe for centuries to treat epilepsy, infertility, hypertension, and arthritis; in European folk medicine, mistletoe has been used for its cardiovascular properties. 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 would place a sprig of mistletoe above the door of their houses as its sacred nature prohibited fighting beneath it; this practice evolved over centuries into the custom of kissing underneath mistletoe at Christmas.(Bryant 1991) In 1921, the Austrian anthroposophical spiritual leader Rudolf Steiner suggested that mistletoe be used to treat cancer, based on the observation that mistletoe, like cancer, is parasitic and lethal to its host.(Ernst 2006) Swiss and German clinics were founded to implement this idea and are still actively using an injectable mistletoe preparation fermented with a strain of Lactobacillus for 3 days, a process more aligned to alchemy and homeopathy than pharmacology.(Ernst 2006, Ribéreau-Gayon 1986)
Extracts of mistletoe can be formulated as unfermented as well as fermented products.(Eggenschwiler 2007, Ribéreau-Gayon 1986, Stein 1998) The chemical composition depends not only on the host tree (eg, apple, elm, oak, pine, poplar, spruce), but also the harvest season and preparation methods. A variety of injectable formulations of mistletoe extracts are currently approved as prescription drugs in Europe, where they are widely used in integrative oncology; injectable mistletoe is not commercially available or approved for cancer patients in the United States.
Chemistry
Alkaloids, flavonoids (ie, quercetin, kaempferol, naringenin), glycosides (ie, anthraquinone, cardiac), lignan sugars, phenolic compounds, phenylpropanoids, saponins, steroids, tannins, terpenes, and viscotoxins have all been isolated from V. album.(Khan 2016)
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.(Samuelsson 1971) 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.(Romagnoli 2000) The viscotoxin profile of the 3 European subspecies of V. album has been determined.(Schaller 1998) Two novel viscotoxins, 1-PS and U-PS, were found in subspecies austriacum (pine) and subspecies abietis (fir). The viscotoxin profile of V. album subspecies did not vary appreciably with 7 different hosts. The American species P. tomentosum yielded a homolog known as phoratoxin.(Becker 1986, Schaller 1998)
Lectins
Viscumin, a toxic lectin, was isolated from V. album and shown to be a type ΙΙ ribosome-inactivating protein.(Olsnes 1982) Three distinct lectins (ML-Ι [viscumin], ML-ΙΙ, and ML-ΙΙΙ) were isolated by another group and shown to have different carbohydrate-binding specificities.(Franz 1981, Müthing 2004) 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.(Soler 1998) The X-ray diffraction 3-dimensional structure of ML-Ι has been obtained in the free state(Krauspenhaar 1999) and bound to beta-galactose.(Sweeney 1993) ML-Ι binds to several sialyl glycoproteins in addition to the galactose-binding specificity initially identified.(Wu 1992, Wu 1995) The structural features important for carbohydrate recognition have been described in detail.(Galanina 1997, Lee 1992) A minor chitin-binding lectin completely distinct from ML-Ι, ML-II, and ML-ΙΙΙ was isolated.(Peumans 1996)
Carbohydrates
The water-soluble polysaccharides of V. album have been purified and characterized. A highly esterified galactouronan and a complex arabinogalactan were identified.(Jordan 1986)
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.(Deliorman 1999, Olsnes 1982) The syringin content of mistletoe growing on different host plants has been measured.(Deliorman 2000) A number of known and novel chalcone and flavanone glycosides have been reported from European V. album.(Fukunaga 1987, Fukunaga 1988) Inositol derivatives, widespread in the Viscaceae family and occurring at relatively high concentrations in all species of mistletoe, are thought to play a role in osmotic balance.(Richter 1992) Other miscellaneous compounds have been reported.(Deliorman 2001, Errenst 1999)
Uses and Pharmacology
Because of the potential toxicity of mistletoe, many studies have been conducted in animals and in vitro. Methodology of clinical trials is generally poor.
Antioxidant effects
Animal and experimental data
Antioxidant properties have been demonstrated for oral mistletoe leaf extract (V. album) in a diabetic rat model.(Turkkan 2016) Additionally, antioxidant and antimicrobial properties of mistletoe stem extract (V. album from oak) for food storage were demonstrated in an experimental study using uncooked ground pork.(Kang 2016) The cosmetic and cosmeceutical effects of V. album (Korean mistletoe) were compared with another species of mistletoe (Loranthus tanakae) and ascorbic acid (positive control). Ethanol extracts of Korean mistletoe demonstrated significantly better radical scavenging activity (P<0.001) than ascorbic acid and exhibited saturation effects greater than 300 mcg/mL. However, when reducing power analysis was performed, V. album extracts (both water and ethanol) showed significantly lower reducing power compared with L. tanakae extracts and ascorbic acid.(Choi 2019)
Cancer
Animal and in vitro data
Experimental and animal data demonstrate direct cytotoxic action (apoptosis induction), immunomodulation, antiangiogenesis, and white blood cell DNA stabilization activity with mistletoe extracts. These include enhanced natural killer cell activity, increased production of interleukins and tumor necrosis factor alpha, activation of mononuclear cells, stimulation of granulocyte phagocytosis, and downregulation of genes associated with tumor progression and invasion.(Bloksma 1982, Büssing 1995, Büssing 1998, Elsässer-Beile 2001, Hajto 1990, Heinzerling 2006, Kelter 2007, Kunze 1998, Kunze 2000, Lee 2007, Lyu 2007, Mueller 1990, Park 2000, Ribéreau-Gayon 1996, Schumacher 2000, Stein 1998, Stein 1999, Tusenius 2005, Wacker 2005) Therapeutic cytotoxic activity is considered to be due to mistletoe lectins; however, viscotoxins and polysaccharides are other cytotoxic compounds that may contribute to these effects.(Eggenschwiler 2007, Horneber 2008) Some in vitro and in vivo experiments suggest that interleukins can stimulate proliferation of certain cancer cells; therefore, mistletoe therapy may not be without risk in cancer patients. Use of mistletoe extracts in patients with primary or secondary brain tumors, leukemia, or malignant lymphoma is contraindicated.(Ernst 2003)
Clinical data
A 2001 prospective, randomized study found no benefit in terms of 5-year survival with postoperative use of oral mistletoe extract in patients with head and neck squamous cell carcinoma.(Horneber 2008, Laccourreye 2017)
Clinical data regarding the benefit of mistletoe for cancer patients are equivocal, and/or many trials have weaknesses, including poor methodology. The vast majority of these trials have been limited to intravenous, subcutaneous, and intratumoral administration of prescription injectable mistletoe formulations, which are beyond the scope of this monograph.
The Society for Integrative Oncology's updated guideline on the evidence-based use of integrative therapies during and after breast cancer treatment (2017) recommends mistletoe be considered for improving quality of life (grade C).(Greenlee 2017)
Cardiovascular effects
Animal and experimental data
Viscotoxins have been shown to induce reflex bradycardia and possess negative inotropic effects in isolated animal cardiac muscle, as well as induce vasoconstriction at higher doses.(Andersson 1973, Rosell 1966) Phenylpropanoids might also play a role in mistletoe's cardiovascular effects through a postulated inhibition of cyclic adenosine monophosphate phosphodiesterase.(Deliorman 2000, Wagner 1986) In contrast to crude V. album fruit, an ethyl acetate extract inhibited potassium-induced contractions in isolated rabbit aorta and partially inhibited phenylephrine-sustained contractions, while its effect on calcium chloride response was similar to that of verapamil.(Khan 2016) In a heart failure rat model, the oral extract of V. album leaf (from common pear) was observed to improve left ventricular ejection fraction, cardiac hypertrophy, and histopathological changes. Regulation of the nitric oxide pathway was suggested.(Karagöz 2016) Similarly, cardioprotective effects of methanol and aqueous extracts of V. album leaf (from Crataegus thorn tree) have been demonstrated in isolated rat models of coronary artery occlusion and reperfusion via nitric oxide–dependent pathways.(Suveren 2017)
CNS effects
Animal data
A review of Viscum species documented animal study data highlighting a variety of CNS activities of mistletoe extracts, including sedative, hypnotic, antipsychotic, analgesic, anxiolytic, and antidepressant effects, with the latter 2 showing equivalence to diazepam 2 mg/kg and imipramine 15 mg/kg, respectively. Improvement was also demonstrated in animal models of Alzheimer disease (V. album from orange; V. album var coloratum) and epilepsy (V. album from citrus).(Szurpnicka 2019)
Cosmetic applications
In vitro data
In a comparative study of the cosmetic properties (antioxidant, antimelanogenic, and antiwrinkle activities) of V. album and L. tanakae extracts (both water and ethanol), the ethanol extract of L. tanakae had higher phenolic content and showed effective antioxidant activity and elastase inhibition. Meanwhile, the ethanol extract of V. album more effectively inhibited tyrosinase. Compared with ethanol extracts, the water extracts of both mistletoes showed lower biological efficacy than the ethanol extracts or no significant effect. These results show that different extracts of mistletoe are associated with different levels of biological activities, presumably because of the differences in phytochemical profiles and because of the different extraction methods used.(Choi 2019)
Diabetes
Animal data
Mistletoe leaf extract (V. album) administered orally in a diabetic rat model showed no effect on blood glucose control.(Turkkan 2016)
Muscle mass loss
Animal and experimental data
Differences in gene expression and protein phosphorylation related to muscle protein degradation and myogenesis have been documented with Korean mistletoe extracts experimentally and in animal models.(Jeong 2017, Lim 2017)
Clinical data
The effect of 1 g and 2 g oral doses of Korean mistletoe extract (standardized to 1.4 to 2.1 mg/g chlorogenic acid) on age-related decline in muscle mass, strength, and physical performance was explored in a 12-week, double-blind, placebo-controlled trial (N=67). Data from the 54 participants who completed the study revealed no significant changes between mistletoe and placebo regarding body weight, muscle mass, or fat mass. In contrast, peak torque knee strength increased significantly in both mistletoe groups compared with placebo (P=0.026) and was greatest in the low-dose mistletoe group.(Lim 2017)
Muscle relaxant effects
In vitro data
Both the crude and ethyl acetate extract forms of V. album have demonstrated smooth muscle relaxant properties in isolated rabbit jejunum.(Khan 2016)
Musculoskeletal effects
Animal and in vitro data
Phoratoxin has demonstrated action on frog skeletal muscle fibers; data suggest that the depolarizing action of the toxin might be attributed to an increase in the nonselective leak current and that it might act as a detergent.(Sauviat 1990)
Osteoarthritis
Animal data
Dietary supplementation with dried Korean mistletoe (V. album from oak; 1 to 1.5 g/day human equivalent dose) was studied for its potential to prevent or delay menopausal symptoms and progression of osteoarthritis in estrogen-deficient obese rats. Little to no benefit was observed in metabolic measures (eg, hot flush reduction, body weight, visceral fat mass, serum glucose and insulin, insulin resistance, bone mineral density). In contrast, a reduction in symptoms of osteoarthritis (eg, limping, swelling, pain) were comparable between mistletoe and the positive control (17beta-estradiol).(Yang 2016)
Reproductive effects
Animal and in vitro data
In an in vitro study to evaluate possible beneficial and/or toxic effects of V. album (from oak) on rabbit spermatozoa, data documented a decrease in rabbit sperm motility in a dose-dependent manner, with up to an 86% reduction after 3 hours compared with control.(Halo 2019)
Dosing
Robust or unequivocal data from clinical trials are lacking to provide mistletoe dosing recommendations for any condition.
An enteric-coated mistletoe–alginate/chitosan microcapsule has been developed to overcome the poor bioavailability of oral mistletoe.(Lyu 2004)
Pregnancy / Lactation
Avoid use. Mistletoe contains toxic constituents.(Brinker 1998, Ernst 2002)
In an in vitro study, a decrease in rabbit sperm motility was demonstrated with V. album (from oak) in a dose-dependent manner, with up to an 86% reduction after 3 hours compared with control.(Halo 2019)
Interactions
A case of a false-positive test for nodal involvement was documented in a 29-year-old patient with Hodgkin lymphoma; the patient had been self-administering subcutaneous homeopathic mistletoe prescribed by her naturopath. Upon discontinuation of mistletoe and repeat scan, total disappearance of abnormal features was observed.(Abreu 2017)
Warfarin: Mistletoe may enhance the anticoagulant effect of warfarin. Monitor therapy.(Moussouni 2022, Schink 2017)
Adverse Reactions
Limited data are available regarding adverse reactions to oral or commercial mistletoe supplements.
Adverse reactions associated with injectable mistletoe dosage forms in clinical trials were predominantly mild to moderate; in some trials, only a few adverse effects were reported, while in others adverse effects occurred in up to 45% of trial participants.(Ernst 2003, Horneber 2008)
Toxicology
Mistletoe is considered to be a toxic plant in humans, with toxic lectin components contributing to toxicity.(Stirpe 1983) Poison control centers report toxicity of the whole plant, but especially the berries. Mild gastroenteritis, seizures, hallucinations, and anaphylaxis have been reported.(Bauer 2005, Courtemanche 2006, Ernst 2001, Spiller 1996)
Index Terms
- Loranthus tanakae
- Phoradendron flavescens
- Phoradendron serotinum
- Viscum coloratum
References
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