A Skeptical Look at St. John's Wort
Stephen Barrett, M.D.
St. John's wort is widely promoted as an antidepressant. However: (a) its use is not supported by high-quality research, (b) its mechanism of action is unknown, (c) the active ingredient, if any, has not been ascertained, and (d) product quality is a serious problem. It began receiving widespread attention after a metaanalysis published in 1996 in the British Medical Journal concluded that it was effective against mild to moderate depression . An editorial that accompanied the report cautioned that longer studies were needed , but the market for St. John's wort products surged anyway.
"St. John's wort" is the common name for the flowering plant Hypericum perforatum. It has many constituents with biological activity, but many of its pharmacological activities are attributable to hypericin, hyperforin, and/or flavonoid constituents . Dosage is usually based on a product's content of hypericin, which varies widely in different parts of the plant, under different growth conditions, and at different times of the year.
The early studies of extracts standardized for hypericin found it to be about twice as effective as a placebo. A few studies found it somewhat more effective than a standard antidepressant. However, none of these studies lasted more than six weeks, which is not long enough to determine how long the herb would be effective or to detect any long-term adverse effects . In addition, some of the studies were not well-designed [3,5]. In most of these studies, the diagnosis was not well established, the placebo response rate was lower than usually seen in such studies, the dosage of standard antidepressants was low, and the dosage of hypericin varied more than six-fold. .
The research on St. John's wort is voluminous and complex, and published analyses are conflicting. The analysis I trust most was published by R. Barker Bausell, Ph.D., a prominent research expert. After reviewing 26 clinical trials that compared St. John's wort to placebo, he noted that only two were conducted in the United States, and both were negative. This is significant, he said, because journals outside of English-speakng countries are much more likely than those in the United States, Canada, Australia and New Zealand to publish undeservedly positive results . The negative studies to which he referred were much larger and better designed than the rest. The first one, which involved 200 participants and was published in 2001, found no benefit against severe ("major") depression . The second study, which involved 340 participants and was published in 2002, found no benefit against moderately severe depression . Both studies, in addition to being larger and longer than the rest, were double-blind, randomized, placebo controlled, and conducted at multiple sites—which is the gold standard for clinical research.
Another study reported in 2008 found that the active ingredient in St. John's wort did not improve the function or behavior of children with ADHD. The study involved 54 children ages 6 to 17, half of whom received hypericin abstract while the others received a placebo. The placebo group did better, but the difference was not statistically significant .
The early research reports on St. John's wort noted no serious side effects, but minor side effects included gastrointestinal discomfort, fatigue, dry mouth, dizziness, skin rash, and hypersensitivity to sunlight . However, in February 2000, the British journal Lancet reported St. John's wort could interfere with the effectiveness of an AIDS remedy (indinavir) ; an immunosuppressive drug (cyclosporin) used to protect patients after heart transplantation ; and an anticoagulant (warfarin) . Based on this study and other reports in the medical literature, the FDA issued a Public Health Advisory stating:
St. John's wort appears to be an inducer of an important metabolic pathway, cytochrome P450. As many prescription drugs used to treat conditions such as heart disease, depression, seizures, certain cancers or to prevent conditions such as transplant rejection or pregnancy (oral contraceptives) are metabolized via this pathway, health care providers should alert patients about these potential drug interactions to prevent loss of therapeutic effect of any drug metabolized via the cytochrome P450 pathway .
Since that time, a few other adverse drug interactions have been noted. St. John's wort should not be used by women who are pregnant or are breastfeeding. Nor should it be used together with standard antidepressants.
Even if future research demonstrates effectiveness, another problem must be overcome before consumers could use St. John's wort effectively. Several studies have demonstrated that many if not most St. John's wort are not trustworthy. In 1998, a Good Housekeeping Institute analysis of six widely available St. John's wort supplement capsules and four liquid extracts revealed inconsistent levels of hypericin and pseudohypericin. The study found:
- A 17-fold difference between the capsules containing the smallest amount of hypericin and those containing the largest amount, based on manufacturer's maximum recommended dosage.
- A 13-fold difference in pseudohypericin in the capsules.
- A 7-to-8-fold differential from the highest to the lowest levels of liquid extracts .
A similar investigation by the Los Angeles Times found that 7 of 10 products contained between 75% and 135% of the labeled hypericin level, and three contained no more than about half the labeled potency .
In 2003, researchers who tested 54 commercial St. Johns wort products purchased in Canada and the United States reported that only two products had a total hypericin content (hypericin plus pseudohypericin) within 10% of the amount stated on the label. The percentage of the label claim varied from 0% to 108% for capsule products, 31% to 80% for tablet products, and total hypericin content of tinctures also varied widely. On average, most products tested contained half of the labeled amount of hypericin .
More recently, ConsumerLab "failed" 6 out of 13 brand-name products it tested. Among the failures, three failed to indicate what part of the plant was used, which is an FDA labeling requirement; four were contaminated with heavy metals; and three contained less than the amount of hypericin or hyperforin listed on their labels .
The Bottom Line
There is no published evidence that St. John's wort is effective against severe or moderately severe depressions, which, in any case, should receive professional help. For mild depression, psychotherapy directed at resolving the cause of the depression would be more prudent instead of, or in addition to, drug therapy.
- Linde K and others. St. John's wort for depression—an overview and meta-analysis of randomised clinical trials. British Medical Journal 313:253-258, 1996.
- De Smet PAGM, Nolen WA. St. John's wort as an antidepressant: Longer term studies are needed before it can be recommended in major depression. British Medical Journal 313:241-242, 1996.
- Barnes J and others. Herbal Medicines, Third Edition. London, England: Pharmaceutical Press, 2007, pp 549-569.
- St. John's Wort. The Medical Letter 39:107-108, 1997.
- Gaster B, Holroyd J. St. John's wort in depression. Archives of Internal Medicine 160:152-156, 2000.
- Bausell RB. Snake Oill Science: The Truth about Complementary and Alternative Medicine. New York: Oxford University Press, 007.
- Sheldon RC and others. Effectiveness of St. John's wort in major depression: A randomized controlled trial. JAMA 285:1978-1986, 2001.
- Hypericum Depression Trial Group. Effect of Hypericum perforatum (St. John's Wort) in major depressive disorder. JAMA 287:2801-1814, 2002.
- Weber W and others. Hypericum perforatum (St John's wort) for attention-deficit/hyperactivity disorder in children and adolescents: A randomized controlled trial. JAMA 299:2633-2641, 2008.
- Piscitelli SC and others. Indinavir concentrations and St John's wort. Lancet 355:547, 2000.
- Ruschitzka F and others. Acute heart transplant rejection due to Saint John's wort. Lancet 355:548, 2000.
- Jobst KA and others. Safety of St John's wort. Lancet 355:576, 2000.
- Lumpkin MM, Alpert S. Risk of drug interactions with St. John's wort and indinavir and other drugs. FDA Health Advisory, Feb 10, 2000.
- Good Housekeeping Institute. New Good Housekeeping Institute study finds drastic discrepancy in potencies of popular herbal supplement. News release, Consumer Safety Symposium on Dietary Supplements and Herbs, New York City, March 3, 1998.
- Monmaney T. Labels' potency claims often inaccurate, analysis finds. Spot check of products finds widely varying levels of key ingredient. But some firms object to testing method and defend their brands' quality. Los Angeles Times, Aug 31, 1998.
- Draves AH, Walker SE. Analysis of the hypericin and pseudohypericin content of commercially available St. John's wort preparations. Canadian Journal of Clinical Pharmacology 10:114-118, 2003.
- Product review: St. John's Wort supplements. ConsumerLab.com, April 8, 2010.
This article was revised on July 31, 2010.