Issue: 68 Page: 50-59
Mistletoe: Good for More Than Free Kisses
by Juanita Evans
HerbalGram. 2005; 68:50-59 American Botanical Council
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.
References
1. Kandela
P. Mistletoe. Lancet.
2001;358(9299):2186.
2. Pliny.
Rockham H, trans. Natural History.
16.250-251. Vol 4. Loeb Classical Library ed. Cambridge: Harvard University
Press; 1938-1963:551.
3. Calder
M, Bernhardt P. The Biology of Mistletoes. Sydney:
Academic Press; 1983.
4. Tainter,
FH. What does mistletoe have to do with Christmas. The American
Phytopathological Society. APSNET
Web site. December 2002. Available at:
http://www.apsnet.org/online/feature/mistletoe/. Accessed September 16, 2005.
5. Viscum.
California Department of Food and Agriculture. Available at:
http://www.cdfa.ca.gov/phpps/ipc/weedinfo/viscum.htm. Accessed September 16,
2005.
6. Sullivan
S. Viscaceae. Species extants: Phylogenetic list of described extant species.
2003. Available at: http://www.speciesaccounts.org/Viscaceae.htm. Accessed
September 16, 2005.
7. Sullivan
S. Loranthaceae. Species extants: phylogenetic list of described extant
species. 2003. Available at: http://www.speciesaccounts.org/Loranthaceae.htm.
Accessed September 16, 2005.
8. Polhill
R, Wiens D. Mistletoes of Africa.
Kew, UK: Royal Botanical Gardens; 1998.
9. Büssing
A. Introduction: History of mistletoe uses. In: Büssing A, ed. Mistletoe:
The Genus Viscum. Australia: Hardwood
Academic Publishers; 2000:1-6.
10. Kirkup
WD, Polhill RM, Wiens D. Viscum in the context of its family, Viscaceae, and
its diversity in Africa. In: Büssing A, ed. Mistletoe: The Genus Viscum. Australia: Hardwood Academic Publishers; 2000:7-30.
11. Ó
hÓgáin D. The Sacred Isle: Belief and Religion in Pre-Christian Ireland. Woodbridge, UK: The Boydell Press; 1999.
12. Smith
DE. History of Mathematics. Vol 1. New
York: Dover Publications; 1951.
13. Pliny.
Rockham H, trans. Natural History.
16.251. Vol 4. Loeb Classical Library ed. Cambridge: Harvard University Press;
1938-1963:551.
14. Ramm
H, Urech K, Scheibler M, Grazi G. Cultivation and development of Viscum
album L. In: Büssing A, ed. Mistletoe:
The Genus Viscum. Australia: Hardwood
Academic Publishers; 2000:75-94.
15. Kimura
T, But PPH, Guo J, Sung CK, eds. International Collation of Traditional and
Folk Medicine: Northeast Asia. Vol 3.
Singapore: World Scientific; 1996:25.
16. Turkington
C, Alper MM. The Encyclopedia of Fertility and Infertility. New York: Facts on File; 2001.
17. Kimura
T, But PPH, Guo J, Sung CK, eds. International Collation of Traditional and
Folk Medicine: Northeast Asia. Vol 4.
Singapore: World Scientific; 1996:7-8.
18. Zhu
Y. Chinese Materia Medica: Chemistry, Pharmacology and Applications. Australia: Hardwood Academic; 1998.
19. Hsu
H. Oriental Materia Medica: A Concise Guide. New Canaan (CT): Keats Pub; 1996.
20. Parrota
JA. Healing Plants of Peninsular India.
New York: CABI Pub; 2001.
21. Amabeoku
GJ, Leng MJ, Syce JA. Antimicrobial and anticonvulsant activities of Viscum
capense. J Ethnopharmacol. 1998;61(3):237-241.
22. Krapp
KM, Longe JL, eds. The Gale Encyclopedia of Alternative Medicine. Vol 3. Detroit, MI: Gale Group; 2001:1194-1196.
23. Moerman
DE. Native American Ethnobotany.
Portland, Oregon: Timber Press; 1998:393.
24. DeSmet
PAGM. Phoradendron Flavescens. In: DeSmet PAGM, Kelles K, Hanser R, Chandler
RF, eds. Adverse Effects of Herbal Drugs.
Vol 3. Berlin: Springer-Verlag; 1992-1997:99-103.
25. Fox
SI. Human Physiology. 7th ed. New York:
McGraw-Hill; 2002.
26. Bruneton
J. Hatton C, trans. Pharmacognosy, Phytochemistry, Medicinal Plants. 2nd ed. Andover, UK: Intercept Ltd; 1999.
27. Fong
WP, Mock WY, Ng TB. Intrinsic ribonuclease activities in ribonuclease and
ribosome-inactivating proteins from the seed of bitter gourd. Int J Biochem
Cell Bio. 2000;32(5):571-576.
28. Huang
Q, Liu S, Tang Y, Jin S, Wang Y. Studies on crystal structures, active-centre
geometry and depurinating mechanism of two ribosome-inactivating proteins. Biochem
J. 1995;309(1):285-298.
29. Au
TK, Collins RA, Lam TL, Ng TB, Fong WP, Wan DCC. The plant ribosome
inactivating proteins luffin and saporin are potent inhibitors of HIV-1
integrase. FEBS Letters.
2000;471(2-3):169-72.
30. Langer
M, Möckel B, Eck J, Zinke H, Lentzen H. Site-specific mutagenesis of mistletoe
lectin: the role of RIP activity in apoptosis. Biochem Biophys Res Commun. 1999; 264(3):944-948.
31. Lim
YT. Mistletoe therapy in endometriosis. Fertil Steril 2002;77(suppl 1):S53.
32. Valentiner
U, Pfuller U, Baum C, Schumacher U. The cytotoxic effect of mistletoe lectins
I, II and III on sensitive and multidrug resistant human colon cancer cell
lines in vitro. Toxicology. 2002;171(2-3):187-199.
33. Pfüller
U. Chemical constituents of European mistletoe (Viscum album L.). In: Büssing A, ed. Mistletoe: The
Genus Viscum. Australia: Hardwood Academic
Publishers; 2000:101-22.
34. Mengs
U, Göthel D, Leng-Peschlow E. Mistletoe extracts standardized to mistletoe
lectins in oncology: review on current status of preclinical research. Anticancer
Res. 2002;22(3):1399-1407.
35. Lavelle
EC, Grant G, Pusztai A, Pfuller U, O’Hahan DT. The identification of plant
lectins with mucosal adjuvant activity. Immunology. 2001;102(1):77-86.
36. Hajto
T, Hostanska K, Weber K, Zinke H, Fischer J, Mengs U, Lentzen H, Saller R.
Effect of a recombinant lectin, Viscum album agglutinin on the secretion of Interleukin-12 in
cultured human peripheral blood mononuclear cells and on NK-cell-mediated
cytotoxicity of rat splenocytes in vitro and in vivo. Nat Immun. 1998;16(1):34-46.
37. Murray
PR, Rosenthal KS, Kobayashi GS, Pfaller MA. Medical Microbiology. 3rd ed. St. Louis, MO: Mosby; 1998.
38. Huber
R, Barth H, Schmitt-Graff A, Klein R. Hypereosinophilia induced by high-dose
intratumoral and peritumoral mistletoe application to a patient with pancreatic
carcinoma. J Altern Complement Med. 2000;6(4):305-310.
39. Blumenthal
M, Busse WR, Goldberg A, Gruenwald J, Hall T, Riggins C, Rister R, eds. Klein
S, Rister R, trans. The Complete German Commission E Monographs: Therapeutic
Guide to Herbal Medicines. Austin, TX:
American Botanical Council; 1998.
40. Perry
LM. Medicinal Plants of East and Southeast Asia: Attributed Properties and Uses. Cambridge: MIT Press; 1980.
41. Manolova
N, Serkedjieva J, Ivanova V. Antiinfluenza activity of the plant preparation
“Broncho Pam” [abstract]. Fitoterapia.
1995;66. (Available from CABabstracts AN# 950315013.)
42. Stoss
M, van Wely M, Musielsky H, Gorter RW. Study on local inflammatory reactions
and other parameters during subcutaneous mistletoe application in HIV-positive
patients and HIV-negative subjects over a period of 18 weeks. Arzneimittelforschung. 1999;49(4):366-373.
43. Gardner
N. Iscador update. AIDA
Treatment News [serial online]. 1998;304. Available at: www.aids.org/atn/i-304.html.
Accessed September 16, 2005.
44. Zheng
YT, Ben KL, Jin SW. Alpha-momorcharin inhibits HIV-1 replication in acutely but
not chronically infected T-lymphocytes [abstract]. Aceta-Pharmacologica
Sinica. 1999;20. (Available from Medline
AN# 10452099.)
45. Büssing A, Stein GM, Pfüller U, Schietzel M. Differential
binding of toxic lectins from Viscum album
L., ML I and ML III, to human lymphocytes. Anticancer Res. 1999;19(6B):5095-5099.
46. Gorter RW, van Wely M, Reif M, Stoss M. Tolerability
of an extract of European mistletoe among immunocompromised and healthy
individuals. Altern Ther Health Med.
1999;5(6):37-48.
47. Riddle
JM. Ancient and medieval chemotherapy for cancer. ISIS. 1985;76(283):319-30.
48. Hippocrates.
Aphorisms. 6.38. In: Hippocrates. Jones WHS, Withington ET, trans. Hippocratic
Corpus. Vol 4. Loeb Classical Library ed.
Cambridge: Harvard University Press; 1923:189.
49. Hartwell
JL. Plants Used Against Cancer: A Survey.
Lawrence, MA: Quarterman Publications, Inc; 1982.
50. Spencer
WG. Introduction to De medicina. In:
Celsus. Spencer WG, trans. De medicina. Vol 1. Loeb Classical Library ed. Cambridge: Harvard University
Press; 1935-38:ix.
51. Celsus.
Spencer WG, translator. De medicina.
5.18.1. Vol 2. Loeb Classical Library ed. Cambridge: Harvard University Press;
1935-38:17.
52. Rather
LJ. The Genesis of Cancer: A Study in the History of Ideas. Baltimore, MD: John Hopkins University Press; 1978.
53. Celsus.
Spencer WG, translator. De medicina.
5.18.6. Vol 2. Loeb Classical Library ed. Cambridge: Harvard University Press;
1935-38:19.
54. Celsus.
Spencer WG, trans. De medicina.
5.18.7. Vol 2. Loeb Classical Library ed. Cambridge: Harvard University Press;
1935-38:19-21.
55. Celsus.
Spencer WG, translator. De medicina.
5.18.15. Vol 2. Loeb Classical Library ed. Cambridge: Harvard University Press;
1935-38:23.
56. Dioscorides.
Wellmann M, ed. De materia medica.
3.89.2 Vol 2. Berlin, reproduction; 1958:104. (Special thanks to John Riddle
for this translation from the Greek for this article).
57. Pliny.
Rockham H, translator. Natural History.
24.6.11-12. Vol 7. Loeb Classical Library ed. Cambridge: Harvard University
Press; 1938-1963:11-13.
58. Ali-Shtayeh
MS, Yaniv Z, Mahajna J. Ethnobotanical survey in the Palestinian area: A
classification of the healing potential of medicinal plants. J
Ethnopharmacol. 2000:73(1-2):221-232.
59. Gabius
HJ, Gabius S. Phytotherapeutic immunomodulation as a treatment modality in
oncology: lessons from research with mistletoe. In: Lawson LD, Bauer R, eds. Phytomedicines
of Europe: Chemistry and Biological Activity.
Washington DC: American Chemical Society; 1998:278-86.
60. Grazi
G. Mistletoe: Introducing an Unusual Plant. Weleda.com. January 1, 1990. Available
at:http://usa.weleda.com/iscador/. Accessed September 16, 2005.
61. Madibela
OR, Letso M, Boitumelo WS, Masedi M, Alton K. Chemical composition of four
parasitic plants harvested over a period of 6 months from two sites in
Botswana. Anim Feed Sci Technol. 2002;95:159-167.
62. Baillon
F. Seasonal variations of respiration, phloem-transport and carbohydrate
content in European mistletoes. Plant Physiology and Biochemistry. 1988;26(1):85-92.
63. Sáenz MT, Ahumada MC, García MD. Extracts
from Viscum and Crataegus are Cytotoxic Against Larynx Cancer Cells. J
Biosci. 1997;52(1-2):42-44.
64. Weber
K, Mengs U, Schwarz T, et al. Effects of a standardized mistletoe preparation
on metastatic B16 melanoma colonization in murine lungs. Arzneimittelforschung. 1998;48(5):497-502.
65. Celsus.
Spencer WG, translator. De medicina.
2.13.2-3. Vol 1. Loeb Classical Library edition. Cambridge: Harvard University
Press; 1935-1938:175.
66. Scott
DF. The History of Epileptic Therapy: An Account of How Medication was
Developed. Carnforth, UK: Parthenon
Publishing Group; 1993.
67. Celsus.
Spencer WG, trans. De medicina. 2.8.11,
2.8.29. Vol 1. Loeb Classical Library ed. Cambridge: Harvard University Press;
1935-1938:137,147.
68. Pliny.
Rockham H, trans. Natural History.
16.244. Loeb Classical Library ed. Cambridge: Harvard University Press;
1938-1963:547.
69. NINDS
Syndeham Chorea Information Page. National Institute of Neurological Disorders
and Stroke. February 2005. Available at:
http://www.ninds.nih.gov/disorders/sydenham/sydenham.htm. Accessed September
16, 2005.
70. Colbatch,
Sir John. A Dissertation Concerning Mistletoe: A Most Wonderful Specifick
Remedy for the Cure of Convulsive Distempers. London; 1730. In: The Lampeter Corpus of Early Modern English Tracts.
Available at:
http://www.tu-chemnitz.de/phil/english/chairs/linguist/real/independent/lampeter/pdf/scia1730.pdf.
Accessed September 16, 2005.
71. Dawes
A. Mistletoe and epilepsy. Ellingwood’s Therapeutist. 1914;8(12):5-8.
72. Rodriguez-Cruz
ME, Perez-Ordaz L, Serrato-Barajas BE, Juarez-Oropeza MA, Mascher D, Paredes
Carbajal MC. Endothelium-dependent effects of the ethanolic extract of the
mistletoe Psittacanthus calyculatus on
the vasomotor responses of rat aortic rings. J Ethnopharmacol. 2003; 86(2-3):213-218.
73. Brookoff
D. Chronic Pain 1: A New Disease? Hospital Practice [serial online]. July 2000. Available at:
http://www.hosppract.com/issues/2000/07/brook.htm. Accessed September 16, 2005.
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