There is considerable public interest in the United States in claims that extracts of the herb St. John's wort (Hypericum perforatum) may be an effective treatment for depression. In Europe Ė where the herb is now widely prescribed Ė a number of studies have been conducted that support the treatment efficacy of certain St. Johnís wort extracts. However, those studies have had several limitations, creating the need for more definitive research.
In response to this need, the National Institute of Mental Health (NIMH) has begun the first large-scale, long-term, controlled clinical trial to assess whether a well standardized St. Johnís wort extract has significant therapeutic benefits for people suffering from major depression. The two other components of the National Institutes of Health (NIH) that are collaborating on the study are the National Center for Complementary and Alternative Medicine and the Office of Dietary Supplements.
The NIH clinical trial will also evaluate the safety of St. Johnís wort, since it is known that although herbs are "natural," they may have side effects and can interact with some medications. For example, a separate NIH study found that St. Johnís wort adversely interacts with an antiviral drug for HIV infection called indinavir (Lancet, Vol. 355, Feb. 12, 2000). In the same journal, Swiss physicians reported two cases of harmful effects from the combined use of St. Johnís wort and a medication to prevent organ transplant rejection called cyclosporine. Thus, though some people believe that herbal treatments are harmless, caution is the best approach until more is known.
Although NIH has undertaken the scientific investigation of St. Johnís wort for the treatment of depression, the non-research use of products containing this herb is not recommended. Once the results of this study are available, NIH will be better able to address the issue of the herbís clinical value, safety, and/or drawbacks.
For people seeking help for depression, NIMH recommends available treatments with proven efficacy and safety, such as prescription antidepressants and/or short-term specific psychotherapies. Research has shown that up to 80 percent of patients respond favorably to these approaches and experience significant symptom relief. Individuals suffering from depression should consult with their doctor about which approach may be most useful for them.
1. What is St. John's wort?
St. John's wort (known botanically as Hypericum perforatum) is a plant with yellow flowers that commonly grows in the wild. In the United States, St. Johnís wort is not a prescription medication, but is sold in health food stores and pharmacies as an herbal tea or nutritional supplement, which the U.S. Food & Drug Administration (FDA) does not regulate.
2. What do European studies of St. John's wort for depression show?
An overview of 23 clinical studies in Europe, published in the British Medical Journal (Vol. 313, August 3, 1996), found that the herb might be useful in cases of mild to moderate depression. The studies, which included 1,757 outpatients, reported that St. Johnís wort was superior to placebo and appeared to produce fewer side effects than standard antidepressants.
3. Why is NIH funding a study on St. Johnís wort for depression if the European results were this promising?
The completed studies are important and have contributed useful information. However, available studies have had several limitations. For example, the doses of the herb given to patients were not always standardized, and the types of extracts differed. Also, the inclusion criteria for study patients varied, which can lead to findings that are difficult to interpret. In addition, the trial durations were not long enough to yield conclusive evidence that St. John's wort is superior to placebo. The NIH-funded trial addresses these limitations. Further, because the study is long-term, it will assess the risk of relapse and the occurrence of extended-use side effects.
4. What does the NIH study involve and how long will it last?
The collaborative study Ė coordinated by Jonathan Davidson, M.D., at Duke University Medical Center Ė includes 336 patients over a 3-year period who have major depression, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. Patients are assigned randomly to one of three treatments: St. John's wort; sertraline (Zoloft), which is a selective serotonin reuptake inhibitor commonly prescribed for depression; or a placebo (or "dummy" pill).
The acute controlled phase of the study will last eight weeks, with a 4-month follow-up of patients who have responded favorably to treatment. The entire study will last three years, and the data analysis is expected to be completed some months later.
5. Are there any dangers in taking St. John's wort?
Many "natural" substances can have harmful effects, especially if taken in large quantities or with other medications. Even too much vitamin A, for example, can be damaging. St. Johnís wort, like certain other herbal treatments, is now known to adversely interact with or change blood levels of particular prescription drugs, such as indinavir and cyclosporine, as discussed above.
Further, NIH findings on indinavir that were reported in the Lancet article, as well as other information in the medical literature, suggest that St. Johnís wort may be an inducer of the metabolic pathway cytochrome P450. Consequently, the combined use of St. Johnís wort and other drugs metabolized via this route could result in harmful effects. These may include oral contraceptives; medications to treat heart disease, depression, seizures, and certain cancers; and those to prevent organ transplant rejection.
For NIH information on the finding, go to http://www.nih.gov/news/pr/feb2000/wgmcc-10.htm. For FDA information, go to http://www.fda.gov/cder/drug/advisory/stjwort.htm. To access the abstract of an article in an earlier issue of Lancet on herb-drug interactions, click on http://www.ncbi.nlm.nih.gov/htbin-ost/Entrez/query?uid=10675182&form=6&db=m&Dopt=b. This abstract is contained in Medline, which is the National Library of Medicineís database of published research. To access other abstracts, go to http://www.ncbi.nlm.nih.gov/pubmed and enter key words such as "St. Johnís wort" or "herb-drug interactions" or "alternative medicines."
Given the research to date, it is evident that "natural" does not always mean "safe." Alternative medical treatments require more research, and people are well advised to seek competent medical supervision before trying them. NIMH also urges individuals who are already taking St. Johnís wort with any of the above types of medications to contact their doctors immediately for medical direction. Health care providers are strongly advised to alert patients to these potential drug interactions, until additional research is done.
Another caution against using St. Johnís wort for the treatment of depression is that the herb is not a proven therapy for the disorder. If major depression is not adequately treated, it can become debilitating and, in some cases, lead to suicide. Proven treatments most commonly used are prescription antidepressants, specific psychotherapies (such as cognitive-behavioral therapy and interpersonal therapy), or a combination of both. Also, because other medical conditions, such as thyroid disorders, can mimic depression, anyone with symptoms of depression should receive a thorough medical examination before beginning any treatment, in order to rule out other possible causes.
6. How can I enroll in the study?
The clinical trial is being coordinated at Duke University Medical Center in Durham, North Carolina, by Jonathan Davidson, M.D. There are 13 study sites throughout the country. Individuals may contact the sites directly (http://hypericum.rti.org/contacts.html) to inquire about participation. Anyone who lives near a site or is willing to travel may apply.
7. Who will be excluded from participating in the study?
People who are taking medications that are metabolized via the cytochrome P450 pathway, such as indinavir and cyclosporine, will not be able to enter this study. Also, severely depressed individuals, especially those who may be suicidal and/or who require hospitalization, or who have taken St. John's wort before and not tolerated it well, are not eligible.
8. Are there side effects involved in taking St. John's wort?
The European studies reported that some patients have complained of mild problems with dry mouth, dizziness, gastrointestinal symptoms, increased sensitivity to sunlight, fatigue, and/or confusion.
9. What are the active ingredients in St. John's wort?
It is not known which components of the herb are active. The extract from St. John's wort contains polycyclic phenols, hypericin and pseudohypericin, in addition to flavonoids (hyperoside, quercetin, isoquercitrin, rutin), kaempferol, luteolin, biapigenin, and hyperforin. Recent data suggest that hyperforin may play a significant role in explaining the effects of hypericum extracts on mood.
10. Why is this study important?
The American public has expressed growing interest in herbal products to treat certain illnesses and wants scientific evidence to support their use. Results of the joint NIMH clinical trial will benefit both patients and clinicians because Ė as a study based on a well-defined sample of adequate size and duration Ė they will help determine if the herb is effective and safe.