Today mistletoe is most commonly known for its ability to procure kisses for anyone who stands under it during the Christmas season. This tradition dates back several thousand years to a time when boughs of mistletoe were hung to protect against evil spirits and to promote fertility.^1,2 Perhaps made possible by their wide distribution, mistletoe species have been used in folk medicine by cultures on almost every continent at some point in history. The use of mistletoe for holiday affection is only a minor example of the various ways in which mistletoe has been used throughout history and in different regions. In the last century, awareness of the medical potential of mistletoe has resurged as its efficacy in treating cancers has been investigated.

The best known species of mistletoe is Viscum album L. in the family Viscaceae. Its rounded leaves are a yellow-green color. It is semi-parasitic, deriving some of its nutrients from the many types of trees on which it grows, including oak (Quercus spp., Fagaceae), apple (Malus spp., Rosaceae), and maple (Acer spp., Aceraceae).³ One of its most notable features is the white berries that ripen during the winter months. This species of mistletoe is commonly found in Europe and parts of the United States. Viscum album appears to be a purposely imported species. In the early 1900s, horticulturist Luther Burbank introduced V. album to California as an ornamental from Eurasia.^4,5 Other mistletoe relatives are native to North America, including species in the genus Phorandendron. However, the term “mistletoe” has been used to refer to a large number of plants from the families Viscaceae and Loranthaceae. There are approximately 400 species in the family Viscaceae and perhaps another 600 species in Loranthaceae.^6,7 These families are differentiated by several morphological features that include pollen shape, chromosome number, type of embryo sacs, and flower size. The distribution of these two families covers every continent except Antarctica. For example, the genus Viscum is found throughout all of Europe, and ranges over most of Africa, Asia, North America, and Australia.^3,8,9,10 All mistletoes are semi-parasitic flowering plants. Some mistletoes grow on the ground and may appear not to be associated with a host plant. However, even these mistletoes are connected by subterranean roots to their host to drain them of nutrients such as water and minerals.³

Surprisingly, although much of mistletoe’s early uses were based on myth and folklore, many of these uses may be supported by the findings of modern science. This paper reviews the historical and scientific evidence for the use of mistletoe species from the families Loranthaceae and Viscaceae in the treatment of disorders concerning the female reproductive system, the immune system, and the nervous system.

Disorders of the Female Reproductive System

The use of mistletoe to increase fertility may be traced back to the time of the Druids in ancient Britain and the European continent. Some of the earliest information on the Druids dates back to a lost work of Posidonius the Apamean, a Greek mathematician who, among other things, wrote about Roman contact with other peoples and cultures during the second century BCE.^11,12 As Roman civilization encroached upon a larger portion of Europe, Druids became an increasingly important subject of interest in literature, and references to them are found in the works of Julius Caesar and Pliny the Elder, among others. Pliny the Elder, a Roman scholar, described one of the Druids’ most important rituals in his Natural History, written in 77 CE. Oak was the most sacred of trees to the Druids. Thus, the mistletoe that grew on this tree was the most sacred of plants because it was believed to have come directly from God. Pliny’s book describes a ritual conducted by white-robed priests who used golden sickles to cut mistletoe from the oak. It was believed that if mistletoe touched the ground, all of its magical and healing properties would be lost. White cloth was used to catch the mistletoe and two white bulls were sacrificed in the process.² This ritual occurred only during the “sixth day of the moon,” a time in which the moon is waxing and is therefore a symbol of fertility.¹¹ Also, Pliny reported that mistletoe would be given to barren animals to promote fertility and could be an antidote to all poisons. On the other hand, Pliny did not appear to give much credence to these uses of mistletoe, as evident by the statement, “So powerful is the superstition in regard to trifling matters that frequently prevails among the races of mankind.”¹³

The Druids were not the only people to use mistletoe for its fertility-enhancing properties. Across the world mistletoe has been associated with the concept of fertility, perhaps because of its growth outside of the typical harvest season of other fruiting plants.⁸ For example, in Europe mistletoe fruits begin to ripen as early as mid-October.¹⁴ In Africa, mistletoe blooms during the peak of the dry season.

Current folk medicine indicates some of the more concrete ways in which the use of mistletoe correlates with an increase in fertility. Several species of mistletoe have been used to deal with various issues of pregnancy. In 1996, the International Collation of Traditional and Folk Medicine was created as a four-volume series containing brief summaries of the uses and actions of a variety of medicinal herbs used in Northeast Asia. One folk medicinal use of V. articulatum Burm.f. in China (where it is known as bian zhi hu ji sheng) was as a topical application to stop uterine bleeding.¹⁵ Uterine bleeding during pregnancy can sometimes be a sign of an impending miscarriage.¹⁶ Similarly, V. coloratum (Kom.) Nakai, has been used in northeast Asia to treat threatened abortions, a condition characterized by vaginal bleeding before the 20th week of gestation.¹⁷ Also, V. coloratum has been used to treat dysmenorrhea (painful menstruation). In these treatments, the mistletoe was prepared through a process that included the cleansing, softening, and drying of slices of the plant that could be taken orally.¹⁷ Taxillus parasiticus (L.) S.T. Chiu, Loranthaceae, syn. Loranthus parasiticus (L.) Merr., has been used to prevent “threatened abortion or vaginal bleeding during pregnancy” in the Guangdong and Guangxi provinces of China.¹⁸ Dried parts of L. parasiticus (hong hau ji sheng in China) and V. coloratum (hu ji sheng in China), which are also commonly called mulberry mistletoe, were also used to stop fetal restlessness (a condition that implies possible miscarriage).¹⁹ Another species of mistletoe, L. amplexifolius Desr., has been used in India to treat menstrual problems. Although the specific nature of the problems is not clarified, the bark of the plant was used in the remedy.²⁰

One study reported the use of V. capense L., in South Africa to treat “excessive or irregular menstruation.”²¹ However, it may be surprising to note that some species of mistletoes were and still are being used to treat amenorrhea (the absence of menstruation).²² Native Americans, such as the Cherokee,²³ have used American mistletoe (Phoradendron leucarpum (Raf.) Reveal & M.C. Johnst., Viscaceae; syn. P. flavescens Nutt. ex Engelm.) to cause abortion. This mistletoe preparation has properties reportedly similar to the hormone oxytocin and has been shown to increase uterine contractions in non-pregnant cats.²⁴ Oxytocin is a protein produced by the hypothalamus that induces smooth muscle contractions of the uterus and the mammary glands, allowing a woman to undergo labor and subsequently lactation to feed her child.²⁵ Dried V. articulatum has been taken orally to treat lactation deficiencies in Traditional Chinese Medicine.¹⁵

Abortifacient properties of these mistletoe species have been attributed to their momorcharins.²⁶ Momorcharins are a type of ribosome inhibiting proteins (RIPs). Ribosomes are the structures found in cells responsible for making proteins. RIPs are cytotoxic to many cell types because they are able to inhibit the final step of protein production, i.e., translation, and thus halt cellular metabolism. Each type of momorcharin displays varying degrees of N-glycosidase and deoxyribonuclease activity as well as the ribonuclease activity.^27,28 Momorcharins were first identified in the fruit and seed of the bitter melon (Momordica charantia L., Cucurbitaceae). These and other RIPs have been found in many of the plants used in Traditional Chinese Medicine, and may account for the variety of effects seen, such as anti-viral, anti-tumor, and embryotoxic activity of these treatments.²⁹ The RIPs in mistletoe are more commonly known as the mistletoe lectins.³⁰

Little research has been done to elucidate mistletoe’s effects on the female reproductive system. The few studies available indicate significant promise that some of these ancient and folk medicinal usages of mistletoe may be sound. For example, in 2002 a research brief was published in Fertility and Sterility indicating that therapy involving subcutaneous and intra-lesional injections of mistletoe extract (species not specified) resulted in an observable decrease in the subjective pain scales of post-hysterectomy patients with endometriosis.³¹ Endometriosis is a condition in which the mucous membranes lining the uterus display abnormal growth patterns in which they can form lesions anywhere in the pelvic cavity. Often the membranes may constrict the organs of the pelvic cavity (e.g., ovaries), release hormones at the wrong time and location, and cause extreme pain.²⁵ The mechanism and action of mistletoe in this treatment is unknown, but the study emphasized the importance of more investigation into the use of mistletoe to treat some of the symptoms of endometriosis.³¹

Disorders of the Immune System

According to Pliny the Elder, during the ritual to gather mistletoe the Druids would say, “Healing all things.”² This suggests that mistletoe was used for more than a therapy for various fertility issues. In recent years, considerable research has investigated the ability of primarily V. album to strengthen the immune system. The mistletoe lectins (ML-I, ML-II, and ML-III) are considered to be the most active biological components of this plant. Lectins are a group of proteins that have a dual activity: binding certain carbohydrate groups and inhibiting translation at the ribosomal level. Studies have demonstrated that isolated mistletoe lectins are responsible for the cytotoxic activity seen in mistletoe extracts. Each ML molecule contains an alpha subunit that can inactivate ribosomes, halt protein synthesis, and ultimately lead to cell death. The beta subunit is responsible for the binding of the lectin.^32,33,34

A study done at the University Hospital Hamburg showed that ML-I was a strong mucosal adjuvant (a compound that is added to a vaccine to help stimulate the mucosal and systemic immune responses). After the DNA sequence of this lectin was obtained, researchers were able to create a recombinant mistletoe lectin (rML) with effects similar to the natural mistletoe lectins. Since the rML can be easily produced and quantified, it may prove to be more useful in future vaccine development than natural mistletoe lectins. However, this study noted that the recombinant lectins were too toxic, and therefore not clinically useful at the present time.³⁵

ML-I has also been shown to increase the number and cytotoxic activity of natural killer (NK) cells.³⁶ Natural killer cells are large lymphocytes in the blood stream that are involved in the innate immune system, and they have the ability to kill any cell covered in antibody, virus-infected cells, and tumor cells.³⁷ Monocytes and macrophages, two types of cells responsible for defending the body by destroying anything that is foreign to it, demonstrated a high affinity for lectins as compared to other lymphocytes, and gene expression and cytokine secretion were increased after 24 hours of incubation with these lectins.³⁶ Cytokines are proteins secreted by lymphoid cells that regulate the immune response³⁷ and are involved in promoting an inflammatory response. Some of these cytokines also promote hemopoiesis,³⁶ the production of red and white blood cells.²⁵

Mistletoe extracts may also enhance the immune system by increasing production of other cell types involved in the immune response. For example, a case study was conducted in which a patient with inoperable adenocarcinoma of the pancreas was treated with intraperitumoral and peritumoral injections of the commercial mistletoe extract Abnobaviscum Quercus 2 (Abvoba Heilmittel GmbH, Pforzheim, Germany) over a five-week period. This particular extract is derived from oak mistletoe and officially licensed in Germany. After the third injection, the patient demonstrated a significant increase in the number of eosinophils,³⁸ phagocytic cells often involved in the allergic response that can defend against parasites.³⁷ These eosinophils were seen in the ducts and tissue around the carcinoma. Although the patient was experiencing a rapid decrease in his condition, a temporary period of stabilization was seen that included no more weight loss during mistletoe extract treatment. This study demonstrated that mistletoe can affect the cell-mediated and humoral immune responses, which are collectively known as the specific immune system. This study’s findings were corroborated with other observations that showed a mild eosinophilia, which corresponds to an increase in the cell types often responsible for allergic reactions and inflammation, in response to mistletoe therapy.³⁸ From these various experiments it can be seen that mistletoe affects a variety of the components of the immune system. This recognition of mistletoe’s wide range of abilities may have been why the German Commission E monograph on mistletoe reported it to be a non-specific stimulator of the immune system.³⁹

There are several ways in which mistletoe’s ability to enhance the immune system has been used in the realms of traditional medicine. For example, in Korea, the twigs and leaves of V. album have been used to treat the common cold.⁴⁰ In Indo-China, V. orientale Willd. has been used to treat children with fevers.⁴⁰ In Taiwan, V. articulatum mixtures have been used against tuberculosis.⁴⁰ Also, L. amplexifolius has been used in India to treat consumption.²⁰ This particular use of mistletoe actually goes against the advice of the Commission E monograph because it says not to use mistletoe for any “chronic-progressive infections” such as tuberculosis.³⁹

Another example of mistletoe’s ability to boost the immune system stems from an herbal combination drug named Broncho Pam, which is used in Bulgaria to treat bronchitis. It contains a mixture of the following herbs: V. album, wild thyme (Thymus serpyllum L., Lamiaceae), sage (Salvia officinalis L., Lamiaceae), peppermint (Mentha x piperita L., Lamiaceae), and licorice (Glycyrrhiza glabra L., Fabaceae). One study infected hen eggs and embryo tissue cultures with strains of influenza virus A, which is known to infect humans. When the eggs and tissue cultures were treated with the drug, viral reproduction decreased. This study demonstrated that mistletoe might act synergistically to relieve the cough and other symptoms associated with “colds.”⁴¹

During the past decade, an increasing number of AIDS (acquired immunodeficiency syndrome) patients have been reportedly using mistletoe extracts, and studies are beginning to investigate the immunomodulatory effects of mistletoe preparations in this patient population.^42,43 Although definitely not a cure, mistletoe extracts may help AIDS patients by enhancing the immune system²² and thus giving the patient some added protection from the secondary infections associated with this disease. The anti-viral capabilities of mistletoe extracts may be attributable to the presence of the mistletoe lectins. Studies done on the momorcharins have shown that some varieties, such as alpha- and beta-momorcharins, inhibit HIV-1 (human immunodeficiency virus) replication. One study suggested that beta-momorcharin can inhibit HIV integrase activity, one of the enzymes necessary for HIV replication, from 50% to 68%, and that this anti-HIV activity is distinct from its ability to inhibit ribosomes.⁴⁴ Another study showed that mistletoe lectins can induce the death of HIV infected cells in a process called apoptosis. In this process, a Fas ligand, a molecule produced by certain lymphocytes, binds to the Fas receptor found on the plasma membrane of other cells. This Fas ligand’s cross-linking with the Fas receptor is a mechanism used by lymphocytes to kill other cells by initiating an apoptotic pathway in the cell expressing the Fas receptor. Mistletoe lectins up-regulate Fas ligand production and down-regulate the concentration of Fas receptors found on normal white blood cells including CD4⁺ T cells, CD8⁺ T cells, and B cells that were isolated from leukemic patients. No change in Fas ligand expression was seen in leukemic lymphocytes, which means that these cancerous cells were more likely to undergo apoptosis (the process of programmed cell death) than the normal cells.⁴⁵ The implication of this research is that the mistletoe lectins may be able to make the patient’s healthy lymphocytes into more potent killers of cancerous cells. This study may help explain another experiment that showed mistletoe treatments enhance the immune system of not only healthy, but also of HIV positive patients.⁴⁶

Perhaps the most significant potential within mistletoe therapy lies in the realm of cancer. As previously mentioned, one study correlated eosinophilia with mistletoe therapy in a patient with pancreatic cancer.³⁸ Today it is known that cancer can result from the body’s inability to survey itself for cell damage. For example, if a cell is dividing uncontrollably, the immune system should recognize those cells and destroy them.²⁵ The Commission E monograph recommends mistletoe as “palliative therapy for malignant tumors through non-specific stimulation.”³⁹ One recent in vitro study showed that all three mistletoe lectins demonstrated cytotoxicity against three different cell lines of human colon cancer. One of the cell lines had an acquired multi-drug resistance. The mistletoe lectins demonstrated even higher activity against the resistant cell line than against the “normal” human colon cancer cell lines, indicating that the mistletoe lectins may specifically target some forms of cancer.³²

Another connection between increased lymphocyte activity and cancer was mentioned in the Hajto et al study. Many advanced cancer patients have a low natural killer (NK) cell activity. Since mistletoe therapies appear to increase NK cell activity, this may be of benefit to some cancer patients. However, many of these patients also display some resistance to certain cytokines, and therefore this result of mistletoe treatment may not be useful.³⁶ More research is required to understand the various interactions between mistletoe therapy and the immune system.

Cancer in Antiquity

The use of mistletoe to treat some types of cancer goes back to antiquity. However, before reviewing the use of mistletoe as an anticancer drug in ancient times, it is important to discuss what the correlation is between cancer as it is currently understood and the cancer of the ancients. A variety of terms were formerly used to describe tumors, lesions, and swellings. The highly revered Persian Muslim scholar and physician Avicenna (980–1037 CE) described cancer as a rapid growth that was painful and throbbing. It would be marked with a distinctive array of darkly colored vessels and these growths were usually insensitive. Ancient writers often described malignant tumors as suppurating (producing pus). They were also careful to distinguish these suppurations from those that occur in response to infections, such as boils and ulcers. However, it is important to note that many terms translated as cancer actually could be so broad in scope as to include malignancies among other abnormal growths. For example, karkinos could have meant malignant lesions, but this was not always the case.⁴⁷ Therefore, the references to cancer treatment and mistletoe therapy in the various translations of ancient works probably correlate with a range of abnormal growths including benign and malignant tumors. Also, one must realize that the recognition of all types of tumors would be mostly on the superficial level. This means the ancients would most likely not have diagnosed or treated most internal cancers. For example, in the Hippocratic work Aphorisms, it is advised to not treat a hidden cancer because the “treatment” would likely harm the patient and decrease his/her lifespan more than letting the cancer run its natural course without therapy.⁴⁸

One of the earliest writers to discuss the use of mistletoe in medicine was the Roman naturalist Celsus. Today, not much is known about the life of Celsus outside of the fact that he probably lived from 53 BCE to 7 CE.⁴⁹ There is much dispute on whether or not he actually practiced medicine or only wrote about it. Nevertheless, his work, De medicina, which is one part of a six-part encyclopedia, is considered a comprehensive look at medicine during ancient Roman times. It incorporates much of the knowledge gathered in the Hippocratic Corpus, the body of approximately 300 medicinal plants and other natural agents attributed to the Greek physician Hippocrates (circa 500 BCE).⁵⁰

First, the use of mistletoe to treat abnormal growths, including possibly cancer, first appears in De medicina when Celsus describes emollients. Emollients are compounds applied topically that are meant to soothe or smooth a wound. According to Celsus almost all emollients were created for the purpose of heating.⁵¹ During the Hippocratic period, cancer was considered “an inflammation of black bile.”⁴⁷ Since black bile is a primarily “cold humor,” it makes sense in the ancient philosophy of humoral medicine that an emollient could treat cancer.⁵² Two emollients of note include the composition of Apollophanes and the emollient of Andreas. The composition of Apollophanes had the property of heating and was used to relieve “pain of all kinds.”⁵³ Most importantly, this emollient was used to “soften indurations.”⁵³ An induration usually describes an abnormally hard area that is most often found on the skin. This emollient contained a variety of ingredients including mistletoe juice, bdellium (Commiphora mukul [Hook. ex Stocks] Engl., Burseraceae), kidney-suet, turpentine-resin, iris root (Iris spp.), and frankincense (Boswellia spp., Burseraceae) soot.⁵³ The actual identities of these ingredients is not definitively known. Also, there are no directions for how to make or administer this emollient. Therefore, the active ingredient(s), if any, cannot be determined with certainty from this preparation.

The emollient of Andreas contained similar ingredients, including mistletoe juice, Cnidian berries (Daphne gnidium L., Thymelaeaceae), wild cucumber (Ecballium elaterium [L.] A. Rich., Cucurbitaceae) root, cardamom (Elettaria cardamomum L. Maton, Zingiberaceae), myrrh (Myrrhis odorata L. Scop., Apiaceae), and bdellium, among many other substances, and it was applied as an ointment. Once again, the active component(s) of this preparation cannot be determined. The emollient of Andreas was used to relax, “draw out humour, [and] mature pus,” which may indicate why it was used against cancer.⁵⁴ Also, it was used to “soften the praecordia [the lower chest in front of the heart] when hard and swollen.”⁵⁴ However, since the emollient of Andreas was also used on abscesses, its effect on tumors or other abnormal growths is difficult to determine.

Celsus also mentions another emollient that contains mistletoe juice that was more active against “scrofulous tumour.”⁵⁵ This emollient also contained ape’s dung, resin, and untreated sulfur in equal parts.⁵⁵ Once again, the putative efficacy of this treatment is impossible to determine from the list of its ingredients alone. Also, it must be noted that mistletoe juice was not always included in emollients against tumors, swellings, or other such abnormal growths. This indicates that if mistletoe could help against some forms of abnormal growths, it may have not been so effective as to be used in all cases.

Dioscorides, the famous Greek physician and herbal authority who wrote De materia medica around 50 to 70 CE, said that mistletoe [Greek: ikos] “has the power [dynamis] to disperse, soften, drawing [or, attracting], and assisting tumors [phumata], tumors of the parotid gland [parôtidas], and other lesions [apostasies] … . When added with frankincence, it softens old ulcers [elkê] and malignant lesions [kakoêtheis apostasies].”⁵⁶ Dioscorides is clearly pointing to mistletoe’s use to treat external cancers, because of his use of the term “malignant,” a distinction that the ancients made on the basis of observable characteristics. To be noted, however, is his use of the verb “softens/malassei” rather than the word for “cures [or, heals/iatai]” which he says of treating “pustules most painful at night/epinuktidas” of the spleen.⁵⁶ Also of interest is that the emollient of Andreas also contained frankincense to soften the praecordia.⁵⁴ Therefore, it can be speculated that mistletoe and frankincense may work together additively or synergistically, although adequate evidence to support this is lacking. Later, in Natural History, Pliny the Elder also wrote that mistletoe is an emollient and can be used to treat tumors, “dries up scrofulous sores,” and “heal inflamed swellings” if mixed with wax and resin.⁵⁷

Mistletoe in Modern Cancer Treatment

Currently, various species of mistletoe are used to treat cancer and other abnormal growths in some traditional indigenous medical practices. For instance, V. capense is used by traditional medicine practitioners in South Africa to treat warts.²¹ Warts are usually caused by viruses that create a localized area of excessive growth of skin cells, which can be likened to a solid benign tumor.³⁷ Also, extracts of V. cruciatum have been used against cancer in Palestine as late as June 1999.⁵⁸

Although from these ancient and modern sources it may appear that the use of mistletoe to treat cancer was haphazard, the current use of mistletoe extracts to treat cancer owes much to mistletoe’s history in traditional medicine. Around 1920, the renowned German philosopher Rudolf Steiner created Iscador®. Iscador is an extract of mistletoe created for the purpose of treating cancer patients. Steiner founded anthroposophy, a mixture of spiritual and religious elements, that was used as a philosophy of living.⁵⁹ However, Steiner may have also recognized that mistletoe was used as an anti-cancer/tumor agent in traditional and ancient medicine.

Much of the scientific research into mistletoe’s effect on cancer resulted from the publicity surrounding Iscador. Today Iscador is marketed by Weleda (Schwäbisch Gmünd, Germany and Congers, NY, USA) and considered to be a complementary therapy, i.e., it is intended for use with conventional cancer treatments such as chemotherapy. According to Weleda, mistletoe therapy is used by nearly 60% of all cancer patients in Germany (Michele Sanz [michele@weleda.com], e-mail, September 22, 2005).

Several commercial brands of mistletoe extracts are available in Europe, including Eurixor®, Helixor® (Helixor Heilmittel GmbH & Co KG, Rosenfeld, Germany), and Vysorel® (Novipharm GmbH, Pörtschach, Austria). These commercial extracts are classified according to how they are made, the species of the host tree the plant grows on, and the time of year in which the mistletoe was harvested. For example, IscadorM® is derived from mistletoe that is grown on apple trees.⁶⁰ This is important because as a parasitic plant, each mistletoe will derive different chemistry from its host and thus potentially different properties.^61,62 Therefore, the particular medicinal properties of any mistletoe preparation may depend on the specie of mistletoe, the host specie, and the season in which it is harvested.

One of the attributes of Iscador and other trademarked mistletoe therapies is the consistent preparation of different formulations. These products are made from one- to two-year-old growths of mistletoe. The samples are separated based on whether or not they were harvested in the summer or the winter months. The entire plant is used to create an aqueous mixture through crushing of its parts and the addition of water. Sometimes, the mistletoe extract is subjected to fermentation for up to 6 weeks. This mixture is diluted to create a stock solution of Iscador that can serve to create dosages of varying strengths. This extract is given usually in one of three ways: intramuscularly, intravenously, or intratumoraly.^59,60 It is not administered orally. Mistletoe therapy may be given once a week or once a day for up to several weeks.

Although the examples presented above represent only a brief look into the effects of mistletoe treatment in cancer, they support the idea that mistletoe causes a change in the immune system. Many of these studies have examined particular chemical constituents of mistletoe. Other studies that have investigated the efficacy of mistletoe treatments have occurred through observations of cancer patients. For example, V. cruciatum extracts have been shown to be cytotoxic to larynx cells through in vitro assays.⁶³ One important in vivo study demonstrated that the mistletoe extract Lektinol® (Madaus AG, Koln, Germany) had “antimetastatic activity against B16 melanoma lung colonization in mice.” When Lektinol was given intravenously each day for 3 weeks, an increase in the number of T cells undergoing maturation and the number of immunocompetent alveolar macrophages was seen.⁶⁴ Therefore, current research such as that summarized here, is demonstrating that mistletoe contains some useful components that may be manipulated into effective drugs in the near future.

Disorders of the Nervous System

Mistletoe also has a long-standing historical record in the treatment of epilepsy and other neurological disorders. In Greco-Roman times, epilepsy was known as the falling sickness. In the Hippocratic Corpus, a strong case was made for the natural rather than divine nature of epilepsy. About one century later, Celsus also discussed epilepsy, describing it as a chronic violent disease that occurs without fever.⁶⁵ Today epilepsy is known as a disturbance in the electrical activity of the brain. Thus, the symptoms manifested depend on which part of the brain is affected.⁶⁶

Even thousands of years ago, the ancients, including the Greeks, Indians, and Chinese, among others, understood that there were a variety of ways in which epilepsy could manifest itself. For example, in De medicina, Celsus mentions that epilepsy is the easiest to cure if the seizures begin before puberty is reached. Also, there was a poor prognosis for treatment of any epileptic fit that began with the head.⁶⁷ D. F. Scott, the author of The History of Epileptic Therapy, noted that the ancient Greeks and Babylonians noticed the phenomena of auditory and visual hallucinations associated with some forms of epilepsy. These events, also called auras, sometimes occur as premonitions to an impending seizure. The ancients recommended that a person experiencing an aura enter a private place immediately to avoid scrutiny and embarrassment.⁶⁶

Pliny was one of the first known authors to mention the use of mistletoe to treat epilepsy. Although there is some discussion on the true identity of this plant, in the Natural History a variety of mistletoe called phaunus is mentioned as being a good purgative for epilepsy.⁶⁸ He also mentions that some people believe mistletoe that has not touched the ground during harvesting can cure epilepsy, which is a direct link to the Druid ritual described previously.⁵⁷

In 1720, Sir John Colbatch re-approached the use of mistletoe to treat epilepsy and other fits such as the St. Vitus’ Dance (now referred to as Syndenham’s chorea.) This disorder is seen in young children with rheumatic fever and is characterized by random aimless uncontrolled movements of the limbs and face. It can last for several months but will spontaneously resolve.⁶⁹

In A Dissertation Concerning Mistletoe: A Most Wonderful Specifick Remedy for the Cure of Convulsive Distempers, Colbatch recounts several of his personal experiences when treating his patients with mistletoe. Colbatch justified the writing of his treatise by citing the idea that mistletoe is an effective and easily attainable treatment for some embarrassing and life-altering conditions. It was his hope that other doctors would use his experience with mistletoe to treat their own patients. He gave instructions on how to properly make and administer mistletoe treatments in case the common people would have to read the treatise to treat themselves. Colbatch experimented with several forms of administration including tinctures, powders, and infusions of the entire mistletoe plant. In one case, Colbatch cited the nightly use of a mistletoe emulsion in curing a young boy of convulsive asthma. Another child who developed a severe case of epileptic fits after recovering from smallpox was also cured through the use of mistletoe over a period of several months.⁷⁰

In the early 19th century, Dr. Edward Sieveking wrote On Epilepsy and Epileptiform Seizures: Their Causes, Pathology and Treatment (London, J. Churchill 1858). According to one account, Dr. Sieveking used mistletoe to treat epilepsy. However, in his book Sieveking mentioned that mistletoe has “proved the slightest influence over the epileptic paroxysm.”⁶⁶ By the latter half of the 19th century, the “miracle drug” for epilepsy was discovered. Bromides proved to be amazingly effective at treating some forms of epilepsy but several decades passed before their use became widespread.⁶⁶ Therefore, the use of mistletoe to treat epilepsy was still being supported by such people as by A. Dawes in Ellingwood’s Therapeutist as late as 1914. Ellingwood’s Therapeutist was a monthly eclectic medicine journal that usually covered topics in herbal medicine. In “Mistletoe and Epilepsy,” Dawes said that mistletoe was the best therapy to treat certain forms of epilepsy because it actually could cure epilepsy and act as an indirect tonic to “tone up the nervous system as well.”⁷¹ He faulted bromides for only sedating the nervous system, because once treatment was stopped, seizures would return.⁷¹ Nevertheless, bromides and the other drugs developed to treat epilepsy were much more consistent in their effects. Therefore, if mistletoe ever had any ability to treat epilepsy and other convulsions, its efficacy undoubtedly was much lower than that of the bromides, and thus its use dropped from common implementation in the medicinal practices of that time.

However, the use of mistletoe to treat nervous conditions, including convulsions, has not disappeared from traditional medicine. In South Africa, V. capense has been used to treat epilepsy and asthma.²¹ Loranthus amplexifolius also has been used to treat asthma in India.²⁰ Some varieties of mistletoe exhibit a hypotensive effect.^22,72 As stated earlier, mistletoe was able to significantly alleviate the pain in some patients with endometriosis. In some oriental areas V. coloratum has been used to treat arthralgia (weakness and neuralgia in the joints). Neuralgia is a spasming or recurring pain that occurs along the length of nerves. Also, V. coloratum has been used to treat beriberi, a form of nerve inflammation caused by a vitamin B1 deficient diet.¹⁷ It is unknown whether this treatment works through a reduction of inflammation or directly on the nervous system. Viscum articulatum has been used for lower back pain and weakness.¹⁵

Several experiments suggest that the use of mistletoe might have had a physiological effect on certain convulsive disorders. One study demonstrated that methanol extracts of V. capense counteracted seizures in mice that were chemically induced by bicuculline and pentylenetetrazole. The chemical bicuculline is able to block gamma-aminobutyric acid (GABA) receptors.²¹ GABA, an inhibitory neurotransmitter, constitutes the largest concentration of neurotransmitter in the brain.²⁵ Therefore, the blockage of the GABA receptor results in over-excitation of nerves and has been implicated in some forms of epilepsy. This study concluded that the anticonvulsive effect of the mistletoe extract may involve GABAergic mechanisms.²¹ The traditional medicinal usages of mistletoe to treat pain might be based on a similar mechanism since GABA is also one of the neurotransmitters involved in decreasing the intensity of pain felt in response to a stimulus.⁷³

Conclusion

Mistletoe was considered a heal-all by the Druids and the history of its use reflects this idea. This paper traced only some of the uses of mistletoe to treat some of the disorders of the reproductive, immune, and nervous systems. In general, mistletoe’s efficacy in some, but perhaps not all, of the diseases mentioned warrants further inquiry. Recent scientific research has shown that the traditional use of mistletoe to treat epilepsy and other convulsions might be warranted. However, considering the plethora of effective pharmaceutical drugs available to treat many of these disorders, mistletoe is not necessarily the “best” option of treatment for epilepsy for all people. On the other hand, the use of mistletoe to treat cancer warrants more investigation. Many of the studies presented have demonstrated that various chemical constituents of mistletoe actually enhance the immune system at least in vitro. Even more promising is the recent flurry of clinical trials involving mistletoe preparations that have shown beneficial effects in areas such as survival time in cancer patients.^{21,29,31,36,38,41,42,46,59,64} Most clinical studies imply that mistletoe therapy bears further examination because it might at least improve the quality of life of some patients. With more scientific investigation, the useful components of mistletoe extracts might be utilized as immune-enhancing components of conventional therapy that also includes the usual routine of chemotherapy, surgery, and/or radiation.

Mistletoe has been used in the traditional folk medicine as the “established” medicinal practices of a variety of cultures from across the world throughout various times in history. Not only do these uses share a striking similarity between these disparate groups, but they also have persisted for over 2000 years. Despite these facts, today the investigation of mistletoe as a therapeutic agent in the treatment of cancer has only just begun. Mistletoe may prove beneficial to current medicine in primary or adjunct treatment of various pathologies. The use of mistletoe therapy in pain management and menstrual problems are only two of the many examples discussed. Presumably, there are many other “unknown” medicinal usages of mistletoe just waiting to be (re-) discovered.

Acknowledgements: The author would like to thank John Riddle, PhD, for the translations found within the article and for his support and guidance.

Juanita Evans currently attends the University of North Carolina at Chapel Hill School of Medicine. She was a Park Scholar at North Carolina State University and graduated with a degree in microbiology. This article was the result of a seminar in the history of medicinal herbs. Contact: Juanita_evans@med.unc.edu.

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