- white-berry mistletoe
- European mistletoe
For Patients & Caregivers
Bottom Line: Mistletoe therapy may improve symptoms and quality of life for cancer patients, but definitive information on these benefits is still lacking.
Mistletoe is a semi-parasitic plant that grows on various host trees. Although some oral mistletoe products are sold as dietary supplements, scientific research has only evaluated intravenous or injected formulations that are not approved as prescription drugs in the United States. Laboratory research shows that mistletoe extracts are able to stimulate the activity of several cells and factors of the immune system. In addition, animal studies show that mistletoe extracts can have anti-tumor activity. Studies in humans show that mistletoe treatment may improve symptoms as well as the ability to tolerate cancer treatments, but most studies on survival improvements do not show significant effects. More rigorous studies are needed to determine whether mistletoe can be considered an effective supportive therapy in cancer care.
- To treat arthritis
There are no data to substantiate this claim.
- To treat cancer and cancer symptoms
Laboratory and animal studies show some anti-cancer activity, but clinical trials have not been able to confirm the same effect in humans. Studies with cancer patients appear to support that mistletoe can improve symptoms and quality of life.
- To treat hepatitis
Clinical trials show conflicting results.
- To treat HIV and AIDS
No scientific evidence supports this use.
- To lower high blood pressure
Laboratory data show that mistletoe may lower blood pressure, but no studies have been done to see whether this could translate into a treatment for high blood pressure.
- As an immune stimulant
Laboratory and animal studies as well as some human studies show that mistletoe can both modulate and stimulate the immune system.
To treat cancer
A few studies on mistletoe therapy for colorectal, melanoma, and head and neck cancer patients have not shown survival benefit. However one study in patients with advanced pancreatic cancer did see both survival and symptom improvements. A few studies have also shown that chemotherapy regimens appear to be better tolerated and not negatively affected when adding a prescribed mistletoe regimen. More studies are needed to confirm these effects.
- Common: Fever, chills, elevated white blood cell count, reaction at injection site, hypersensitivity
- Less common, may indicate toxicity: Diarrhea, vomiting, headache, low blood pressure, low heart rate, fainting or passing out, increased blood sugar, itching, rash
Most reactions to infusions under medical care were mild to moderate. Rare instances of severe toxicity, reactions, or even death have occurred with self-administration or by ingesting other forms of mistletoe.
For Healthcare Professionals
Mistletoe is a semi-parasitic plant that grows on various host trees. Extracts of this plant are used for a variety of conditions including cancer, HIV, hepatitis, and degenerative joint disease. Oral preparations are available as dietary supplements and homeopathic remedies. However, research reported in the literature has only evaluated parenterally administered formulations thus far, which are not approved for use in the United States by the Food and Drug Administration.
In animal models, mistletoe injections attenuated airway inflammation and eosinophil infiltration (1). An injectable form of mistletoe lectins reduced frequency and intensity of clinical signs and symptoms of hepatitis C (2), although little has been added to the literature since this earlier study. There are no published trials evaluating mistletoe for HIV or arthritis.
Mistletoe extracts have been noted to have anticancer effects in animal models (3)(4). Earlier studies in humans support the use of mistletoe for cancer supportive care to improve symptoms, reduce chemotherapy and radiotherapy side effects, and prolong survival (5)(6)(7). Epidemiologic data also suggest a survival advantage following mistletoe treatment (8)(9).
In more recent studies, simultaneous exposure of various cancer cell lines to mistletoe extract along with doxorubicin, gemcitabine, docetaxel, or cisplatin does not appear to inhibit chemotherapy and may produce additive effects (10). In human studies, mistletoe improved cancer-treatment related toxicities in patients with advanced non-small cell lung cancer (11) and colorectal cancer (12), and reduced symptoms and improved quality of life (QoL) in patients with pancreatic (13) and breast (14) cancers. In two studies with 5-year follow-ups of breast cancer patients, mistletoe did not appear to negatively influence chemotherapy efficacy (14) and appeared to continue reductions in persistent symptoms (15). Mistletoe administered in conjunction with gemcitabine in patients with advanced solid tumors allowed higher gemcitabine doses to be used without apparent effects from mistletoe on gemcitabine pharmacokinetics (16). Although mistletoe appeared to prolong survival in patients with locally advanced or metastatic pancreatic cancer (13), no significant survival effects were found in older studies for patients with metastatic colorectal cancer (17), melanoma (18), or head and neck cancer (19).
Raw mistletoe contains toxic constituents. Possible adverse effects from mistletoe treatment include injection site reactions, chills, and fever (16)(20). Long-term use may also reduce T-cell function in cancer patients (21), but the majority of adverse reactions were mild to moderate and dose-related (22). Because mistletoe inhibits CYP3A4 in vitro, it could theoretically interact with drugs metabolized by this enzyme (23).
Mistletoe lectins are the most investigated single component of mistletoe extracts, with cytotoxic effects attributed in part to ribosome-inactivating properties and apoptotic induction (5). Lectins induce macrophage cytotoxicity, stimulate phagocytosis of immune cells, increase TNFα, IL-1, IL-2, and IL-6 cytokine secretion, and enhance cytotoxicity effects on various cell lines in vitro (29). In lymphoblastic leukemia cells, mistletoe extracts stimulate dendritic cell maturation and activation (30) and induce dose-dependent apoptosis through caspase-8 and -9 dependent pathways (26). In animal models, triterpene-containing mistletoe extracts produced the greatest induction of apoptosis (26) and appeared to improve efficacy against malignant melanoma compared with conventional mistletoe extracts via reduced tumor angiogenesis (31). Viscotoxins from mistletoe are also thought to be responsible for immunostimulant and tumor-inhibiting activities (28). However, mistletoe has been shown to produce both pro- and anti-proliferative effects depending on dose (32).
Mistletoe preparations induce T-helper 2 immune response, as evidenced by significant eosinophilia during treatment in patients with chronic hepatitis C (2). Mistletoe-induced immune stimulation may explain the physical improvements that contribute to reported improvements in cancer patient QoL (5), although others counter that there is no clear mechanistic explanation as to why non-specific immune activation should enhance antitumor activity, even as increased neutrophil counts are held to be a satisfactory endpoint (25).
Individual serum concentrations of natural mistletoe lectins from a commercially available mistletoe preparation injected in healthy volunteers varied widely, with mean and median peak concentrations at 1 and 2 h post-injection respectively, and some subjects with detectable concentrations 2 weeks thereafter (20).
Common: Injection site reactions, fever, flu-like symptoms, leukocytosis (16)(20)(22)
Uncommon: Diarrhea, nausea, vomiting, headache, increased blood glucose, decreased blood pressure, syncope, generalized pruritus, urticaria (22); bradycardia , organ toxicity (33)
Long-term use: Reduced T-cell function in cancer patients (21)
Other: In animal models, hypotension and bradycardia with crude extracts (34)
The majority of adverse reactions to infusions were mild to moderate, dose-related, and did not require treatment in a large multicenter, observational study of cancer patients (22).
Subcutaneous inflammation mimicking metastatic malignancy: In a 61-year-old breast cancer patient 2 months post-surgery, induced by mistletoe injections self-administered over 12 months (35).
Fatalities: Rare, and due to excessive ingestion of mistletoe teas (33)(36).
Cytochrome P450 3A4 substrates: Mistletoe inhibits CYP3A4 and may therefore affect the intracellular concentration of drugs metabolized by this enzyme, although clinically relevant systemic or intestinal interactions with CYP3A4 were considered unlikely (23).
Troger W, et al. Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: a randomised clinical trial on overall survival. Eur J Cancer. 2013;49:3788-3797. doi: 10.1016/j.ejca.2013.06.043
In this prospective, open-label phase III study, patients with advanced or metastatic pancreatic cancer were randomized to subcutaneous mistletoe injections or no additional treatment along with best supportive care (BSC) for both groups. A dose-escalation (0.01–10 mg), thrice-weekly administration schedule was used for mistletoe injections. Group-sequential analyses was pre-planned to occur after 220, 320 and 428 patients met off-study criteria. Participants were stratified into predefined good- or poor-prognosis groups. Overall survival (OS) at 12 months was assessed as the primary endpoint. At interim analysis (n=220), median OS was significantly longer for mistletoe compared with BSC-only patients (4.8 vs 2.7 months respectively; prognosis-adjusted hazard ratio, HR=0.49; P<.0001). When evaluated by subgroups, good-prognosis median OS was 6.6 versus 3.2 months (HR=0.43; P<.0001), and poor-prognosis median OS was 3.4 versus 2.0 months respectively (HR=0.55; P=0.0031). Frequency and severity of symptoms that included pain (96.9%), loss of energy (70.9%), weight loss (42.5%), nausea/emesis (18.9%), diarrhea (2.4%), and anxiety (2.4%) were significantly lower for intervention-group patients (P<.0001 for each parameter except diarrhea [P=.0033] and anxiety [P=.046]). No mistletoe-related adverse events were observed. The study indicates thus far that mistletoe may prolong survival in some pancreatic cancer patients and reduce disease-related symptoms. Secondary endpoint results that include QOL and concomitant medications will be published separately.
Bar-Sela G, et al. Mistletoe as complementary treatment in patients with advanced non-small-cell lung cancer treated with carboplatin-based combinations: a randomised phase II study. Eur J Cancer. 2013;49:1058-1064. doi: 10.1016/j.ejca.2012.11.007
A total of 72 patients with advanced non-small cell lung cancer were randomized to receive mistletoe extract with first-line carboplatin-based chemotherapy (n=33) or chemotherapy alone (CT; n=39) thrice weekly until tumor progression to evaluate any benefits on treatment-related side-effects and QoL. A majority of patients had Stage IV disease (65%) and squamous histology (62%). There were no differences in median OS between groups. More control patients had CT dose reductions (44% vs 13%, P=.005), Grade 3/4 non-hematological toxicities (41% vs 16%, P =.043), and hospitalizations (54% vs 24%, P=.016). Although the addition of mistletoe therapy did not improve total adverse events or QoL, the benefits to other treatment-related toxicities warrants further study.