Mistletoe (Viscum album L.): A Comprehensive Reference
1. Identity, Botanical Classification, and Natural Source
Viscum album L. is a species of mistletoe in the family Santalaceae, commonly called European mistletoe, common mistletoe, or simply mistletoe. It is native to Europe, as well as western and southern Asia; it is found only rarely in North America, as an introduced species.
Viscum album is an extremely specialized perennial flowering plant that has evolved to live as a parasite on its hosts' aerial parts. It is classified as a hemi-parasitic plant of the Santalaceae family. It is an obligate hemiparasitic evergreen plant that grows on the branches of various trees and is connected to the xylem of the host tree, through which it obtains water, minerals, and to some degree organic compounds.
The plant features leathery green leaves with parallel veins, small yellow unisexual flowers in 3-flowered cymes, and dioecious inflorescences usually consisting of three flowers, with female flowers generating white fleshy berries in which a seed is embedded in the mucilaginous mesocarp, normally containing two embryos.
The genus Viscum encompasses multiple species of medicinal interest. Plants commonly known as mistletoe correspond to different perennial dicotyledonous angiosperm species belonging to the Rosales order, with the most recognized species included in the genera Viscum, Phoradendron, Arceuthobium, Peraxilla, Loranthus, Amylotheca, Amyema, Taxillus, Psittacanthus, and Scurrula, spread throughout different botanical families.
Three subspecies of Viscum album are recognized on the basis of host preference: V. album subsp. album, subsp. abietis, and subsp. austriacum, which show characteristic differences in their phytochemical compositions. Viscum album L. is a semi-parasitic evergreen that grows on a variety of host trees including apple, oak, lime, and poplar, and is native to much of Europe and parts of Western Asia, thriving in temperate climates where it forms rounded clumps high in tree canopies.
Common Names and Synonyms
- Viscum album subsp. album is commonly known as European mistletoe, gui (French), Mistel (German), vischio (Italian), or muรฉrdago (Spanish).
- American mistletoe (Phoradendron flavescens) is the species that grows in the United States and is used as a romantic holiday decoration, while European mistletoe (Viscum album) is the species that has been used for centuries in traditional herbal medicine.
Common Preparations and Dosage Forms
Viscum album L. preparations can be divided into phytotherapeutic extracts standardized on a certain lectin level (brand names such as Cefalektin, Eurixor, Lektinol) and anthroposophical/homeopathically produced extracts (brand names such as AbnobaViscum, Helixor, Iscador, Iscucin, Isorel).
In addition to oral preparations, sterile injectable preparations are available from several companies in Europe and the United States, since mistletoe is widely used as an adjunctive treatment for cancer. According to the recommendations of the manufacturers, the preparations are usually administered two to three times a week by subcutaneous injection in increasing dosages. Mistletoe extracts are also increasingly administered intravenously, intratumorally, or intracavitarily.
The numerous complex ingredients found in mistletoe extracts vary widely in type and amount depending upon the species of mistletoe, the location where the plant is grown, the time of year when the plant is harvested, the particular host tree, the extraction procedure used, and a number of other factors.
2. Traditional and Historical Use
Ancient and Celtic Traditions
Ancient Celts revered mistletoe as a sacred symbol of peace and fertility; druids harvested it with golden sickles from oak boughs during winter solstice ceremonies, believing it conferred protection and healing. The use of mistletoe in ritual form is mainly related to traditions of Celtic druids, the ancient civilization of people living on the British Isles, in what is now Ireland and Scotland.
The ancient Romans linked mistletoe with peace and love, displaying it over doorways to protect the building. Before becoming a festive favorite, mistletoe was highly valued in ancient Greek, Roman, and Celtic culture.
Classical and Medieval Scholars
The two major mistletoes are mentioned in classical sources such as Dioscorides and Pliny, and by medieval European practitioners such as Paracelsus, and Arab physicians such as al-Kindi, al-Ghafiqi, and Ibn al-Baytar.
Roman naturalist Pliny the Elder (1st century CE) documented Viscum album's gall-forming effects on livestock and its occasional use as an antispasmodic. In medieval Europe, herbalists such as Hildegard von Bingen recommended mistletoe preparations for epilepsy and rheumatism, with a decoction of twigs and leaves in wine said to calm convulsions.
Ethnomedicinal Uses by Region
In ethnopharmacology, mistletoe was used in the treatment of CNS disorders such as epilepsy, hysteria, nervousness, nervous spasms, hysterical psychosis, dizziness, and headaches.
- In India, a tea prepared from mistletoe leaves was used to treat diabetes.
- In Africa, Viscum species were used as a remedy to treat diarrhea and as an enema for stomach troubles in children.
- In Israel, Viscum cruciatum Sieber ex Boiss. was commonly used to treat constipation in young children and adults.
- Mistletoe was also used against general pain, backache, and arthritis. In Egypt, the plant was used for the treatment of epilepsy, arteriosclerosis, and diseases of cardiac arteries, and as a hypotensive.
- Contemporary traditional medicine uses of mistletoes are found in Lebanon, Israel, Egypt, Turkey, and Pakistan.
- Research into Asian mistletoes has reported positive effects of Korean mistletoe in cases of hypertension, ulcers, epilepsy, inflammation, wounds, and nephrotic disease.
The Anthroposophical Era
In 1916, Rudolf Steiner mentioned for the first time mistletoe extracts as a possible therapy for cancer. V. album subsequently gained notable attention due to its central role as a leading remedy in cancer care in Anthroposophic medicine. In German-speaking countries, mistletoe has been used as complementary anticancer therapy for more than 100 years.
3. Key Constituents and Active Compounds
At least 250 different compounds have been reported across twelve Viscum species, including amino acids and peptides, alkaloids, phenolic acids, flavonoids, terpenoids, carbohydrates, fatty acids, lipids, and other types of compounds. Such varied pharmaceutical applications result from the rich chemical composition of Viscum species, which largely depends on the host species. The main active compounds are lectins, viscotoxins, flavonoids, phenolic acids, sterols, lignans, terpenoids, phenylpropanoids, alkaloids, and fatty acids.
Mistletoe Lectins (ML-I, ML-II, ML-III)
A broad range of biologically active substances have been identified in Viscum album L., including viscotoxins, flavonoids, triterpene acids, and mistletoe lectins. Commercial aqueous Viscum album L. extracts contain the hydrophilic mistletoe lectins (ML) IโIII, which are the best-studied compounds from mistletoe.
Mistletoe lectins consist of a toxic A-chain โ the site-specific ribosome-inactivating N-glycosidase โ and a carbohydrate-binding subunit B. The B-chain is important for cellular lectin uptake and internalisation of the A-chain, and is partially involved in the induction of cytokine synthesis, but does not induce apoptosis on its own. The cytotoxic and apoptosis-inducing effect of ML is exerted by the ribosome-inactivating A-chain.
The cytotoxic A-chain inhibits the elongation step of protein biosynthesis by catalysing hydrolysis of the N-glycosidic bond at adenine-4324 in the 28S RNA of the 60S subunit of ribosomes, resulting in apoptosis or necrosis. The immunomodulatory activity of mistletoe lectin is attributed to the B-chain, manifested by enhancing the secretion of cytokines and the activity of natural killer cells.
ML-I is known to have a broad influence on the immune system, with increased levels of interleukins, TNF-ฮฑ, interferon-ฮณ, and granulocyte-monocyte colony-stimulating factor, as well as increased activity of macrophages and NK cells demonstrated in vitro and in vivo. These immunostimulatory effects are exerted at low-dose ML-I (1โ10 ng/mL), whereas higher doses (above 100 ng/mL) abrogate these effects by inducing apoptosis in leucocytes.
Viscotoxins
Present in the foliage and fruits of V. album, and in other related species, are low-molecular-weight proteins of the thionin type, called viscotoxins, as well as characteristic lectins called viscolectins, both of which contribute to its defense system and can be found in extracts and related products.
Quantitative analysis of the viscotoxin isoforms A1, A2, A3, B, 1-PS, and U-PS in fresh mistletoe plant material showed that the pharmaceutical processing specific for the preparation of Iscador warrants a high yield of viscotoxins, with no degradation or transformation during the production process.
Viscotoxins can increase the number of circulating natural killer cells and consequently improve the host's antitumor immunity. Viscotoxin also has an effective immunomodulatory impact on human and animal granulocytes and acts on cellular apoptosis.
Triterpene Acids
The hydrophobic triterpene acids โ oleanolic, betulinic, and ursolic acid โ represent another potent group of mistletoe-derived substances, although their low solubilities exclude them from commercially available aqueous extracts. The blood pressure-lowering activity of mistletoe extracts may have been due to the presence of these triterpenoids, such as oleanolic acid and betulinic acid.
Flavonoids and Phenolic Acids
The plant contains large amounts of active components such as lectins, viscotoxins, phenylpropanes, lignans, flavonoids, amines, and polysaccharides, with demonstrated antioxidant, anticancer, anti-inflammatory, and antibacterial properties, as well as antidiabetic, antiepileptic, immunostimulatory, and antiviral activity.
Viscum album flavonoids have been shown to reduce tachyarrhythmias and to normalize electrical conduction through the Purkinje fibers, thereby decreasing ventricular excitability. They have also been shown to reduce noradrenalin-induced aortic contractions.
Polysaccharides and Other Compounds
Viscum album L. contains various bioactive compounds including lectins, viscotoxins, flavonoids, polysaccharides, alkaloids, terpenoids, tannins, phytosterol, phenolic acids, resins, saponin, and organic acids. The phytochemical profile โ and thus the pharmacological potency โ varies substantially by host tree species, geographic origin, and harvest season.
4. Established Mechanisms of Action
Apoptosis Induction
The mechanisms underlying the anti-tumoral activity of Viscum album or mistletoe lectins are complex and involve apoptosis, angiogenesis, and immunomodulation. Viscum album preparations (Iscador) consist of aqueous extracts from different types of European mistletoe; biologically active components include mistletoe lectins and viscotoxins.
The RNA glycosidase activity of the alpha subunit of mistletoe lectins causes possible damage to involved cells by inactivating the ribosome and inducing apoptosis. Further studies have clarified that "direct apoptosis induction by mistletoe lectins occurs only after uptake of the molecules into the cell due to the action of the ribosome-inactivating A-chain."
In vitro and ex vivo treatment of Ewing sarcoma cells with mistletoe extract inhibited proliferation and induced apoptosis in a dose-dependent fashion, with a synergistic effect observed upon combination treatment. Apoptosis occurred via both intrinsic and extrinsic apoptotic pathways, evidenced by activation of both CASP8 and CASP9.
Immunomodulation
Treatment with Viscum album extracts or with purified mistletoe lectin has been shown to be associated with tumor regression in several in vivo experimental models of tumoral implantation. The mechanisms underlying the anti-tumoral activity involve apoptosis, angiogenesis, and immunomodulation in various cell types, including lymphoblastoid, monocytic, and endothelial cell lines.
The immunomodulatory activity of ML I was investigated in vitro by measuring cytokine release. At concentrations of low cytotoxicity, ML I showed immunostimulatory activity on peripheral blood mononuclear cells (PBMCs) and THP-1 cells. RT-PCR confirmed that cytokine induction by ML I is regulated at the transcriptional level, suggesting that both apoptosis and cellular signaling are induced by the same concentration range of ML I.
In advanced oral cancer, local injection of mistletoe extract resulted in stimulation of dendritic cells and activation of macrophage polarization followed by induced cytotoxicity. Clinical studies have demonstrated that mistletoe treatment induced increased granulocyte and eosinophil counts, lymphocytes and NK cells, and levels of several pro-inflammatory cytokines.
Cardiovascular and Antihypertensive Mechanisms
Studies on myocardial ischemia and reperfusion injury in rats, as well as isoproterenol-induced heart failure in rats, confirmed that the cardioprotective effect of Viscum album L. may be mediated by upregulation of the NO (nitric oxide) pathway. Studies in L-NAME-induced hypertensive rats treated with methanolic extract of Viscum articulatum showed that mistletoe has an antihypertensive effect, which may be attributed to its diuretic, nephroprotective, and hypolipidemic action.
5. Scientific Evidence by Area of Use
5.1 Oncology (Cancer Support and Complementary Therapy)
Mistletoe is one of the most widely studied complementary and alternative medicine (CAM) therapies for cancer. In certain European countries, preparations made from European mistletoe (Viscum album) are among the most prescribed drugs offered to cancer patients.
The findings from more than 50 clinical trials of mistletoe extracts in patients with cancer have been published, and several systematic reviews and meta-analyses of the results of these studies have been performed. Three of the most recent systematic reviews addressed quality of life (QOL), survival, and symptom relief in patients with various cancer types.
Quality of Life
Most studies reported an improvement in QOL. In one systematic review that examined 26 randomized controlled trials (RCTs), 22 trials reported an improvement in QOL. Most studies reported improvement in QOL dimensions such as fatigue, sleep, appetite, anxiety, nausea, pain, and general physical, emotional, and functional well-being.
Survival
A systematic literature review found 49 publications on the clinical effects of Iscador usage on survival of cancer patients meeting inclusion criteria; among them, 41 studies and strata provided enough data to extract hazard ratios. The majority of studies reported positive effects in favour of Iscador application. Funnel plots were considerably skewed, indicating publication bias. A random-effect meta-analysis estimated the overall hazard ratio at HR = 0.59 (CI: 0.53 to 0.66, p < 0.0001).
Reports of improved survival and/or quality of life have been common, but many of the studies had major weaknesses that raise doubts about the reliability of the findings. At present, the use of mistletoe cannot be recommended outside the context of well-designed clinical trials. Such trials will be valuable to determine more clearly whether mistletoe can be useful in the treatment of specific subsets of cancer patients.
Fatigue
A meta-analysis determined the impact of mistletoe extracts as a pharmacological treatment for the management of cancer-related fatigue, including randomized clinical trials and non-randomized studies of interventions in cancer patients, with cancer-related fatigue severity or prevalence as an outcome and testing of mistletoe extracts compared to control groups. One meta-analysis showed a non-significant effect of mistletoe extracts on the fatigue subscales of quality of life questionnaires.
Phase I Intravenous Trial at Johns Hopkins
A phase I trial (ClinicalTrials.gov identifier: NCT03051477) tested intravenous Helixor-M in patients with solid tumors to determine its safety and maximum tolerated dose (MTD). Tumor responses, serum cytokines, tumor markers, and quality of life were also measured. The Johns Hopkins Phase I trial established intravenous administration safety at 600 mg three times weekly.
Randomized Trial in Breast Cancer
A monocentric controlled trial with 95 patients was randomized into three groups at the National Cancer Research Center of Serbia, comprising breast cancer patients (stage T1โ3N0โ2M0) undergoing surgery and adjuvant chemotherapy. Two different European mistletoe extracts (Helixor A, Iscador M Spez) were injected three times per week during 18 weeks of chemotherapy. Mistletoe extracts were safe in this clinical study. Subcutaneous injections did not induce fever, nor did they influence the frequency of relapse and metastasis within 5 years. This result suggests that mistletoe extracts had no adverse interactions with the anticancer agents used. Furthermore, certain side effects of chemotherapy decreased under this complementary treatment in breast cancer patients.
Non-Small Cell Lung Cancer โ Emerging Evidence
Real-world evidence from over 400 non-small-cell lung cancer patients showed that combining mistletoe with PD-1/PD-L1 inhibitors doubled median overall survival (6.8 to 13.8 months), with biomarker-selected populations experiencing up to a 91.2% reduction in death risk. This finding, while potentially significant, derives from observational real-world data and requires confirmation in prospective randomized trials.
FDA Regulatory Status
The FDA has not approved the use of mistletoe extract as a treatment for cancer or any other medical condition.
5.2 Blood Pressure and Cardiovascular Effects
Preliminary trials carried out using oral mistletoe have found it can reduce the symptoms of high blood pressure, particularly headaches and dizziness; however, mistletoe has a small (if any) effect on actually lowering blood pressure. Evidence from human clinical trials remains limited and somewhat preliminary for this indication.
Viscum album L. subsp. album is recognized as a medicinal plant due to its beneficial effects, including anti-tumor activity, antioxidant, anti-inflammatory, anti-hepatotoxic, hypoglycemic, and antimicrobial properties as well as for lowering blood pressure. However, the bulk of evidence supporting cardiovascular effects comes from animal and in vitro studies rather than human clinical trials.
5.3 Central Nervous System โ Anticonvulsant and Neurological Effects
The main chemical constituents of Viscum L. species relevant to CNS activity are viscotoxins, lectins, flavonoids, phenolic acids, terpenoids, sterols, phenylpropanoids, and alkaloids. Various extracts of Viscum album L. showed central nervous system activity, including antiepileptic, sedative, antipsychotic, anxiolytic, antidepressant, and antinociceptive effects in mice and rats.
In a mouse experiment, a mistletoe extract was protective against pentylenetetrazole- and bicuculline-induced seizures. Madeleyn reports six cases of infantile spasms, one 9-year-old child, and two adult patients with epilepsy who became seizure-free on Viscum album treatment. These are preliminary, low-quality data points; robust human clinical trials on mistletoe's neurological effects are not yet available.
5.4 Antidiabetic Effects
Viscum album (mistletoe) has been documented as a traditional treatment of diabetes. In acute 20-minute tests, 1โ10 mg/mL aqueous extract of mistletoe evoked a stepwise 1.1- to 12.2-fold stimulation of insulin secretion from clonal pancreatic B-cells. The ability of the extract to enhance insulin secretion did not depend upon the use of heat during extract preparation and was not mediated by lectins. These results demonstrate the presence of insulin-releasing natural product(s) in Viscum album, which may contribute to the reported antidiabetic property of the plant. This evidence is limited to in vitro and animal models; human clinical evidence for an antidiabetic effect is lacking.
5.5 Antioxidant and Anti-Inflammatory Activity
Major evidence strongly suggests immunostimulant, anti-inflammatory, and antibacterial activity, confirming the properties already reported for the European mistletoe. Studies have shown that crude leaf extracts of plants harvested from the host Juglans regia L. exhibited higher yields of phytochemical constituents and noticeable antioxidative properties, with the ethanolic leaf samples reporting the highest phenols (13.46 ยฑ 0.87 mg/g), flavonoids (2.38 ยฑ 0.04 mg/g), and DPPH radical scavenging (87.26% ยฑ 0.30 mg/mL). These are laboratory findings; well-controlled human trials on antioxidant outcomes are absent.
5.6 Immunomodulation in Healthy Subjects
Numerous studies in humans have shown immunomodulatory effects of mistletoe preparations, with reasonably good evidence from controlled clinical trials that mistletoe preparations improve quality of life during chemotherapy.
6. Body Systems and Health Areas Associated with Mistletoe
Mistletoe has been used as a treatment for many diseases in traditional and folk medicine. To date, anticancer, immunomodulatory, cardiac, antidiabetic, hepatoprotective, neuropharmacological, antibacterial, and antifungal properties of mistletoe extracts have been studied most extensively.
- Oncology / Immune System: Adjunct cancer therapy; immunomodulation via NK cell, cytokine, and lymphocyte pathways.
- Cardiovascular System: Traditional use for hypertension; preliminary evidence for vasodilatory and cardioprotective effects in animal models.
- Central Nervous System: Traditional use for epilepsy, anxiety, and headache; antiepileptic effects demonstrated in animal models only.
- Endocrine / Metabolic System: Traditional antidiabetic use; in vitro evidence for insulin secretagogue activity.
- Gastrointestinal System: Traditional use for diarrhea and constipation in various cultural contexts.
- Musculoskeletal System: Traditional use for arthritis and rheumatism.
- Reproductive System: Traditional use in some cultures for fertility-related conditions.
7. Dosage Forms and Dosages Reported in Studies
In one randomized controlled trial, participants received Iscador Quยฎ in increasing dosage from 0.01 mg to 20 mg or placebo injections subcutaneously three times per week.
In a pilot study on gastric carcinoma patients, abnobaVISCUM (aVQ) was injected subcutaneously three times a week from postoperative day 7 to week 24 with increasing doses: 8 injections of 0.02 mg, followed by 8 injections of 0.2 mg, 8 injections of 2 mg, 8 injections of 20 mg, and then continued with 20 mg until the end of the study. This schedule corresponds to the recommended treatment schedule of the manufacturer.
Helixor-P was evaluated in a phase I trial with weekly intravenous infusion, with a dose escalation from 200 to 2,000 mg, and the maximum tolerated dose (MTD) was not reached. The Johns Hopkins Phase I trial established intravenous administration safety at 600 mg three times weekly.
In clinical routine, treatment with mistletoe extracts is often individualized by adjusting the concentration, the manufacturing method, and the mistletoe type to the patient response.
Clinically, mostly lower dosages than 2,000 mg Helixor P have been applied in cancer patients.
8. Safety, Adverse Effects, and Drug Interactions
General Safety Profile
Although mistletoe plants and berries are considered poisonous to humans, few serious side effects have been associated with mistletoe extract use.
Of 1,923 cancer patients treated with subcutaneous mistletoe extracts, 283 patients (14.7%) reported 427 expected effects (local reactions <5 cm and increased body temperature <38ยฐC). Adverse drug reactions (ADRs) were documented in 162 (8.4%) patients who reported a total of 264 events. ADRs were mild (50.8%), moderate (45.1%), or severe (4.2%); all were non-serious. ADR frequency increased as mistletoe dose increased, while fewer ADRs occurred during mistletoe therapy received concurrently with conventional therapies.
Common Adverse Effects
Adverse events included local reactions at the injection site and flu-like symptoms such as fever, chills, fatigue, mild gastrointestinal symptoms, and headache.
Anaphylaxis Risk
Case reports of anaphylaxis to viscotoxins of mistletoe extracts have been documented in the medical literature (Bauer et al., Ann Allergy Asthma Immunol, 2005; Hutt et al., Allergol Immunopathol, 2001). The viscotoxin fraction has been specifically implicated in serious allergic reactions.
Hepatotoxicity
In several small, rather short-term clinical trials, mistletoe in conventional oral doses was typically described as having no adverse side effects, with no mention of either hepatotoxicity or ALT elevations. Isolated reports of serum enzyme elevations during mistletoe therapy have been listed in large national registries, but usually without details of timing, duration, and severity. In multiple trials of parenteral mistletoe extracts and purified or recombinant viscumin, liver injury and ALT elevations were not described. In the rare cases of clinically apparent liver injury attributed to mistletoe, the European form was used and patients were also exposed to other potential hepatotoxic herbs, making the role of mistletoe uncertain. Thus, mistletoe has not been shown convincingly to cause clinically apparent liver injury, at least in the doses used in humans.
As liver enzymes have not been investigated in all intravenous studies and the database is currently too small to allow firm conclusions on which intravenously applied doses can cause elevation of liver enzymes, monitoring of liver enzymes in patients receiving intravenous treatment has been suggested.
Plant Toxicity
All parts of mistletoe are toxic to humans, with the leaves and stem being more poisonous than the fruits. Ingestion of raw plant material โ especially the berries โ is associated with toxicity, distinct from the standardized, prepared extracts used in clinical settings.
Drug Interactions
In an in vitro study, each dose of respective chemotherapeutic drugs was combined with Viscum album extract (VAE) in clinically relevant concentrations and proliferation and apoptosis were measured. VAE did not inhibit chemotherapy-induced cytostasis and cytotoxicity in any experimental setting; at higher concentrations, VAE showed an additive inhibitory effect. The in vitro results suggest that no risk of safety from herb-drug interactions is to be expected from the simultaneous exposure of cancer cells to chemotherapeutic drugs and VAE. This is an in vitro finding and cannot be extrapolated directly to human clinical interactions.
In an observational cohort study, three types of mistletoe extract (Iscador, Helixor, and abnobaVISCUM) were found to be safe in a small group of cancer patients with autoimmune diseases.
Evidence Quality and Limitations
Extracts from European mistletoe (Viscum album L.) have been used as complementary cancer therapy since the 1920s. To date over 160 clinical studies on mistletoe in cancer therapy have been conducted with varying quality; the therapy is still controversial.
Previous systematic reviews have suggested positive effects of mistletoe extract on quality of life and chemotherapy toxicity, but no survival benefit, and these randomized controlled trials suffered from methodologic deficits.
Seven out of 14 controlled clinical trials also show improvement of survival; however, because of heterogeneity and shortcomings of the studies, no firm conclusions can be drawn.
Pharmacological activities of mistletoe have been investigated mainly for crude extracts. It remains a new field for scientists to determine which chemical compounds are responsible for the individual biological activities of mistletoe and how these activities are achieved.
References
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