By Natalia Morales D.

People may mostly know mistletoe as a parasitic plant that is hanged on doorways during Christmas time as an assurance of marriage and a prediction of long life and happiness. However, mistletoes have not always been associated with kissing. Records of the medicinal use of mistletoe to treat diverse ailments come before the time of Christ. Even Pliny the Elder describes in his book, Natural History, how Celtic Druids used it as a remedy for poisons and to ensure fertility. Today, interest in Viscum album L. has been mostly focused on its use as a CAM (complementary and alternative medicine) in cancer patients and here in general as a treatment complementing mainstream medicines. Since its introduction as a cancer treatment in the 20th century, several clinical trials have been performed to address symptom relief, quality of life, and survival in patients with cancer. Although quality of life has been the outcome mostly reported by these studies, more clinical trials need to be carried out in order to assess the safety and efficacy of V. album L. as a complementary therapy for cancer patients.

Introduction

Since ancient times Viscum has been a mistletoe well-known in Europe, Asia, and Africa (Maul et at., 2019). The genus Viscum has been traditionally placed in the family of Viscaceae. However, recently, it has been shown in genetic research by the APG II (The Angiosperm Phylogeny Group, 2003) that Viscum is better placed within the Santalaceae (Rao, 2014).

Mistletoe produces sugars via photosynthesis and takes nutrients and water from the trees it hosts. It grows in a variety of wooded habitats extending from the temperate regions to the tropics (University of Oxford, 2010). Mistletoes distribution ranges from North Africa to southern Scandinavia and southern England, across Central Europe to east and southwest Asia as well as to Japan (Kew Science, 2020). In Europe, there are three subspecies (ssps), that are differentiated depending on the host tree where they grow. V. album spp. abietis grows on fir trees (Abies), V. album ssp. album on hardwoods and V. album spp. laxum on spruce and pines (Kew Science, 2020). Species also include the Korean (V. album L. coloratum) and the American (Phorandendron serotinum). However, the majority of investigative work has been done on European mistletoe, V. album L. (Rao, 2014).

V. album L. (V. album), is an evergreen, hemiparasitic, perennial flowering plant that generally grows on the branches of a variety of trees as well as on conifers. In the UK, it mostly occurs in southern and central England and around London; and commonly grows in lime, apple, poplar and hawthorn trees (Kew Science, 2020). Moreover, European mistletoe has been highly valued as a medicinal plant due to its alleged therapeutic activity in hypertension therapies and cancer (Maul et at., 2019).

V. album is a small spherical woody shrub with a diameter of about 1 metre wide, similar to a bird’s nest. It grows on the branches of its host tree, and it is attached by a haustorium (slender projection of the parasitic plant). The stem is smooth and yellowish and freely forked (Kew Science, 2020). The leaves are tongue-shaped, at about 1 to 3 inches long, very thick, and leathery, with entire margins. They are arranged in pairs, and there is a flower-bearing top at the end of each forked part. The flowers are inconspicuous, greenish-yellow colour and small. They open in May and are produced in close short spikes of three to five flowers in the forks of the branches (Grieve, 2020). V. album is dioecious, and the flowers are either male or female. They are also produced in separate plants, and neither of them has corolla. The female flowers have four petals and quadridentate calyx. The male flowers, on the other hand, have no calyx, and stamina is almost connate to the petals with anthers as pores (Grieve, 2020). Despite being small, the flowers are insect-pollinated, and they are believed to produce nectar and to be sweetly scented. Furthermore, V. album’s fruit is a smooth, globular white berry that appears from October until May and is ripened in December. Inside them, they contain a sticky pulp that surrounds an uncoated green seed (Paine and Harrison, 1992).

Traditional and modern uses

V. album L., unlike other plants, never touches the earth and blossoms during the cold season. That is why, before the time of Christ, Celtic Druids considered it a sacred symbol with both medicinal properties and magical powers. Pliny the Elder, a Roman scholar, described Druids’ rituals in his book Natural History written in 23AD-79AD. On the sixth day of the new moon after the winter solstice, Druids used a golden sickle to cut mistletoe from the tree. Branches were caught in a white cloth as they fell taking care that the plant did not touch the ground. It was believed that if mistletoe fell upon the ground, all its healing and magical properties would be lost (Evans, 2005). Branches of mistletoe were distributed to the people, who hung them over doorways to ward off from witches and ghosts (Bussing, 2004).

Druids also believed mistletoe to be a remedy for poisons and to ensure fertility, as well as to possess properties with the ability to cure each illness (Bussing, 2004). Even today, mistletoe is a symbol of love and innocence. The modern tradition of kissing under the branches of mistletoe during Christmas may also have roots in the old myths (Jorgensen, 2008). This exchange of kisses is interpreted as an assurance of marriage and prediction of long life and happiness.

Hence, V. album L. has been used for several thousands of years in diverse human cultures. One of the first records of its use as medicine comes from the time of Hippocrates (460-377 BC) who used this plant to treat ailments of the spleen and complaints associated with menstruation (Zänker and Kaveri, 2015). Celsus (25 BC- 50 AD) in the fifth book of De Medicina, described V. album as an ingredient that could be used in combination with other substances to reduce pain or swelling, suppuration or to treat carcinoids, abscesses, or scrofula. There is also evidence that Pliny the Elder mentioned as beneficial for treating infertility, epilepsy, and ulcers (Zänker and Kaveri, 2015).

Furthermore, V. album has been used in local medical traditions for the treatment of hypertension, spam of the heart, diarrhoea, headache, rheumatic pain, sore throat, and lumbago (Bussing, 2004). Recent interest in V. album L. began in the 20th century when it was introduced as a cancer treatment by Rudolf Steiner, the founder of anthroposophic medicine. Since then, clinical evaluation of V. album extracts as a cancer treatment has expanded (Ostermann and Bussing, 2012). Consequently, sterile aqueous extracts of V. album are now available in the market under diverse brand names and are administered subcutaneously for the treatment of cancer in continental Europe, and especially in Germany. However, in the UK, only mixed preparations are available in the market. In the European market, V. album is also registered as a herbal tea or as a combination product to treat mild cardiovascular problems (European Medicines Agency, 2012).

Unlike in many European countries, in the United States, these extracts are not considered to be safe when used parenterally (National Cancer Institute, 2020). The FDA (Food and Drug Administration) does not allow its use against cancer unless it is used by approved clinical trials (Ernst, 2011).

Pharmacology: Preclinical and clinical data

Since mistletoes are semi-parasitic plants, the composition of an extract varies depending on the host tree, season, parts of the plant used and extraction method. Nowadays, V. album L. is among the most common herbal extracts used in cancer treatment (Kienle et al., 2009). It contains active components known as lectins, viscotoxins and alkaloids. These active components have apoptotic and cytotoxic effects. However, it also contains another group of compounds such as phenolic acids, flavonoids and phenylpropanoids, which have anti-inflammatory and antioxidant activities (Nazaruk and Orlikowski, 2016). In addition to this, other components in mistletoes include phytosterols, triterpenes, oligo and polysaccharides (Nazaruk and Orlikowski, 2016). However, of all these active components, lectins have been the most rigorously investigated (Kienle et al., 2009). Lectins have shown to cause cell apoptosis and to display cytotoxic effects on multidrug-resistant cancer cells. They also improve the cytotoxicity of anticancer drugs (Kienle et al., 2010).

In animal models, V. album demonstrated to inhibit cell growth and increase DNA stability (Bussing, Regnery and Schweizer, 1995). Also, it has been suggested that V. album may decrease the side effects of chemo- and radiotherapy and may prevent the effects of immune suppressor drugs (Rentea, Lyon and Hunter, 1981; Kuttan et al., 1993). V. album aqueous extract exhibited tumour growth inhibition, immunomodulation, and reduction of metastases in tumour bearing mice (Zarkovic et al., 2004). In addition to this, a study carried out by Podlech et al. (2012) noted that injection of aqueous V. album extract in tumour exerted considerable reduction in tumour growth as compared to subcutaneous injection of the same (Podlech et al., 2012). However, studies on the effects of mistletoe on cancer cell growth have given rise to mixed and inconsistent results. Some of the differences in results may have been due to the difference in route of administration, the number of cells used or different doses of aqueous V. album extracts.

More than 50 clinical trials of V. album extract in cancer patients have been published. Also, numerous meta-analyses and several systematic reviews of the results of these studies have been performed (National Cancer Institute, 2019). Studies have addressed symptom relief, survival, and quality of life in patients with different cancer types, but most of the studies only reported improvements in quality of life. Osterman et al. (2009) analysed 49 studies employing a widely used licensed medicine with a well-defined chemical profile using different methodologies (Ostermann et al., 2009). In these studies, the authors found apparent favourable effects of this product on patients’ survival in comparison to no treatment. Nevertheless, the evidence demonstrated the presence of bias as this review only focused on randomised trials; thus, the effects were no longer significant (Ostermann et al., 2009). Moreover, Braedel-Rouff (2010) evaluated the effects of this product on the activity of natural killer cells and found that most of these trials showed beneficial effects. However, it was suggested to carry out further investigation as evidence was not compelling (Braedel-Ruoff, 2010).

Horneber et al. (2008) reviewed 21 RCTs (randomised clinical trials) which assessed the quality of life, tumour response and psychological distress in patients with various cancer types. Patients were given V. album preparations either alone, with radiation therapy, or chemotherapy (Horneber et al., 2008). Of the 21 RTCs 13 provided data on survival, 16 on quality of life, and 7 on tumour response. Accordingly, 6 of the 13 trials showed some evidence on survival, but none of them was of high methodological quality. On the other hand, 14 of the 16 trials showed some evidence on quality of life. However, only 2 of them were of higher methodological quality. Furthermore, few side effects were shown and depended on the dose of mistletoe extracts. The evidence from RTCs to support the effects of V. album extracts on survival or on its ability to fight cancer is rather weak. Nevertheless, there is still some evidence that V. album extracts may benefit the quality of life on breast cancer patients during chemotherapy (Horneber et al., 2008).

Another systematic review carried out by Kienle et al., (2010) evaluate controlled clinical trials on the effectiveness and efficacy of V. album for quality of life in cancer patients. The authors identified 26 RCTs and 10 non-RCTs (Kienle, 2010). All of the non-RTCs reported benefits on the quality of life. And among the 26 RCTs, 22 reported benefits on quality of life, 3 showed no difference and 1 did not outline any results (Kienle, 2010). In this systematic review, it was concluded that V. album extract has an impact on the quality of life. Also, it reduces the side effects of chemotherapy and radiation, such as nausea, vomiting, fatigue, depression, and emotional well-being.

Toxicity, side effects

Few adverse effects have been reported from the uses of mistletoe extracts. Subcutaneously, mistletoe extract can cause soreness and inflammation at the site of the injection, fever, chills, and headache (Ernst, 2011). Also, few cases of severe allergic reactions, such as anaphylactic shock, have been reported (Hutt et al., 2001). It rarely causes swelling of regional lymph nodes. According to manufacturers, mistletoe preparation should be avoided in case of hypertension, acute inflammatory disease, hypersensitiveness, or autoimmune disorders (Helixor, 2020). It is presumed that mistletoe therapy may interact with chemically defined drugs. It should not be administered simultaneously with other immunotherapies, and its injection with other drugs must be avoided to prevent changes in the efficacy (Helixor, 2020).

Conclusion

V. album L. is one of the most widely investigated complementary medicines in cancer therapies. In Europe and especially in Germany, V. album has become one of the most prescribed drugs for patients suffering from cancer. Thus, several clinical trials have been carried out in order to determine V. album’s effects on quality of life, survival, stimulation of immune system, and symptoms relieve. However, quality of life has been the outcome mostly reported by these studies. Also, few side effects have been reported, and they are usually linked to the dosage quantity.

Although V. album has been found to be safe and therapeutically effective in most of the clinical trials, many of these studies also present significant design weaknesses. Thus, more rigorous and improved studies on V. album as a complementary therapy for cancer patients need to be performed in order to assure its safety and efficacy.

© Natalia Morales D. 2020. All rights reserved.

Natalia Morales D., MSc Medicinal Natural Products and Phytochemistry 2019-2020 (student), Research Cluster ‘Biodiversity and Medicines’/Centre for Pharmacognosy and Phytotherapy, UCL School of Pharmacy, Univ. London, 29-39 Brunswick Sq., London WC1N 1AX

In this essay, we do not intend to advise or recommend herbs for medicinal or health use. This information is intended for educational purposes only and should not be considered as a recommendation or an endorsement of any particular medical or health treatment. The use of any such product should be based on the appropriate advice of a health care professional or based on the information available in the patient information leaflets (i.e. for THR products).

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