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By Ayan Kayal, Yale University
Popular in Europe, especially Germany, St. John's wort is an herbal remedy, derived from a common flowering plant. Given the rising numbers of Americans using complementary and alternative medicine, research on St. John's wort appears particularly important. Review of meta-analytical studies suggests that St. John's wort is a safe and effective remedy for mild to moderate forms of depression, as shown by placebo trials. Furthermore, St. John's wort appears to be an effective remedy as compared to allopathic antidepressants, as shown in various trials. There are conflicting reports regarding the use of St. John's wort for severe depression. Further research is also necessary for long term use of the herb.
St. John's wort is an herb that has been used therapeutically for over 2000 years. Commonly used for treating depression, St. John's wort is part of the Hypericaceae family. The herb is also used homeopathically and is known under its scientific name of Hypericum perforatum in that realm. St. John's wort has gained popular acceptance as a remedy for depression that has lower side effects than traditional antidepressants, such as SSRIs.
The common name of the plant is derived from its use in ceremonies for St. John the Baptist. The Old English word for plant is "wort." Described as a "common roadside plant" in the United States, the herb has also been used for nervous conditions, including sleeplessness. The herb grew 10 times in retail from $20 million in 1995 and $200 million in 1997 in the United States alone, but is also commonly used in Europe, especially Germany.
Recent scientific studies have questioned the popular use of St. John's wort for depression. In order to fully understand the use of St. John's wort for depression, a brief overview of the use of complementary and alternative medicine (CAM) is helpful. Because the scientific mechanisms of St. John's wort have not been adequately identified and isolated, the herb falls under the heading of complementary and alternative medicine, as far as allopathic doctors in the United States are concerned. However, in continental, St. John's wort is licensed for use in treating depression and anxiety, and is an over the counter drug in the United Kingdom.
Next, while it is known that St. John's wort is used for depression, some question what types of depression for which it can be used or if it is effective at all. Furthermore, while many studies have compared St. John's wort to placebo, some trials have also been conducted using allopathic antidepressants, such as imipramine, fluoxetine (Prozac), and sertraline (Zoloft). Studies also compare the side effects reported by subjects receiving St. John's wort as opposed to allopathic antidepressants. This paper intends to review and synthesize several studies that have been done on St. John's wort as well as assess its efficacy in addition to proposing possible directions in future research.
Surveys estimate that approximately 42% of U.S. consumers used CAM in 1997. A study by Eisenberg et al. (1998) conjectured that 427 million visits to CAM specialists were made in 1990, which increased to approximately 629 million in 1997, surpassing the visits to conventional physicians. The same study also estimates that the amount spent on visits to CAM practitioners was higher than that spent on hospitalizations, and total costs for CAM were somewhere between $27 billion and $34.4 billion, which is about equal or higher to that spent for allopathic doctors.
While allopathic medicine use far surpasses CAM use for life threatening issues, CAM use is higher for chronic medical conditions, such as chronic pain, addictions, arthritis, urinary tract problems, back problems, and headaches. CAM therapies are also frequently used for psychological conditions such as anxiety and depression. CAM therapies commonly used in the United States include homeopathy, chiropractic therapy, acupuncture, massage, and herbal medicine.
Among herbal therapy, besides St. John's wort, other popular herbs include gingko (Gingko biloba) for improved memory, ginseng (Panax ginseng) for energy, kava (Piper methyisticum) for stress and anxiety, and valerian (Valeriana officinalis) for stress and anxiety as well. Herbal remedies are not classified as drugs by the FDA and therefore are not regulated as such. Considered dietary supplements, they are loosely overseen only by the United States Pharmacopeial Convention, Inc., which develops standards for "quality, purity, storage, and shelf life." Herbal remedies are not held up to quality-control standards by the FDA, and therefore can sometimes contain inconsistent amounts of active ingredients.
St. John's wort has been tested in numerous clinical studies. A few meta-analytical studies have also looked some of the studies' methodologies and results. One of the main reasons for investigating the use of St. John's wort appears to be its relatively low incidence of side effects, as compared to conventional allopathic antidepressants. These side effects may include drowsiness, dry mouth, constipation, sweating, and dizziness as well as sexual dysfunction. The most common side effect for St. John's wort subjects appears to be dry mouth, but very few subjects report having any.
The consequence of the side effects is that subjects on conventional antidepressants tend to drop out of studies more frequently than those on St. John's wort. For example, in the meta-analytical study by Linde and colleagues, 0.8 percent of St. John's wort patients dropped out as a result of side effects, as compared to 3.0 percent of those receiving allopathic antidepressants. In addition, 19.8 percent of St. John's wort patients reported side effects. Close to twice as many patients in the allopathic antidepressant groups showed side effects, at 35.9 percent. In other studies, these side effects have shown to be even stronger, with 3 percent dropping out in the St. John's worth group and 16 percent dropping out in the imipramine group.
In placebo trials in the Linde et al. study, 0.4 percent of St. John's wort subjects dropped out, as compared to 1.6 percent of placebo subjects. The numbers of subjects reporting side effects is even closer for the two groups, at 4.1 percent of St. John's wort subjects and 4.8 percent of placebo subjects. The numbers do not appear to be statistically distinct from each other.
The main evidence for the support of St. John's wort comes from a number of randomized controlled double-blind placebo studies, as well as randomized controlled double-blind studies that compared St. John's wort to allopathic antidepressants, most frequently imipramine. Most of these studies involved the treatment of mild to moderate depression.
One of the most common tests for depression is the Hamilton depression (HAMD or HAM-D) scale. The Hamilton scale uses 17 items to evaluate the level of depression, based on somatic responses. A newer Hamilton scale uses 21 items. Studies generally determine that a patient has responded to a treatment if they rate fifty percent less than their baseline score, if they rate less than ten, or both. A score between 14 and 20 is considered to demonstrate mild depression, while a score between 21 and 25 demonstrates moderate depression.
A less commonly used depression test is the clinical global impressions test, which scores patients on three factors: severity of illness, global improvement, and efficacy. Subjects given an evaluation of "much improved" or "very much improved" are considered to have had an effect. Linde and colleagues cite these two scales for depression in their meta-analytical study as the "most consistently used instruments." This scale ranges from one to seven, ranging from "very much improved" to "very much worse," respectively.
The results for the studies involving mild and moderate depression appear to be astounding. The meta-analytic studies have focused on the trials for St. John's wort with adequate rigor of methodology in randomized controlled double-blind placebo trials, double-blind allopathic antidepressant trials, or a combination of the two. Linde et al. found 13 suitable placebo studies for analysis. About 22.3 percent of subjects were affected by treatment in the placebo sample, while 55.1 percent of subjects in the St. John's wort sample. The pooled ratio was 2.67 for the two groups. These numbers are statistically significant at an alpha rate of 0.05.
When measured in the three conventional antidepressant trials, St. John's wort was shown to be 63.9 percent effective. Allopathic antidepressants showed an efficacy of 58.5 percent, with a pooled ratio of 1.10. Two more studies involved the use of combinations of St. John's wort with valeriana in place of simply St. John's wort. These studies had a more pronounced difference, with the St. John's wort combinations showing 67.7 percent efficacy, while allopathic antidepressants were 60 percent effective, with a pooled ratio of 1.52. These numbers are statistically the same within 95 percent confidence intervals.
Subsequent meta-analytical studies have confirmed the results of the Linde et al. study. Kim and colleagues found a 73.2 percent success rate for St. John's wort. The success rate for placebo was only 37.9 percent. Similar, when compared to the tricyclic antidepressants, maprotiline, amitriptyline, and imipramine, St. John's wort had a success rate of 64 percent, while 66.4 responded to the tricyclics.
Gaster and Holroyd found statistically significant p-values on three out of the four placebo studies, all with an alpha rate of less than 0.001. St. John's wort subjects responded favorably on the HAMD scale for all four of the placebo studies. When compared to tricyclics, three studies showed p-values that were insignificant, indicating comparable efficacy for St. John's wort and maprotiline, amitriptyline, and imipramine. The third of these studies, with imipramine, showed efficacy of St. John's wort for severe depression.
One of the latest papers, by Kasper, cited various studies involving both placebo trials and allopathic antidepressant trials. Kasper cites studies involving fluoxetine. One study found a reduction in HAMD score of 55 percent for fluoxetine, as compared to 53 percent for St. John's wort. A placebo-fluoxetine study also found that 16 percent of placebo subjects showed a significant drop in HAMD score, while 29 percent of fluoxetine subjects and 33 percent of St. John's wort subjects did. Kasper also cites a study that compared St. John's wort successfully to sertraline. This shows similar efficacy to selective serotonin reuptake inhibitors, as well as tricyclics.
While a study cited by Gaster and Holroyd involved the successful use of St. John's wort for major depression, two recent studies refute this notion. A placebo study by Shelton and colleagues found no significant reduction in HAMD for St. John's wort subjects. The main difference found between placebo and St. John's wort was a significant difference in remission rate for a particular subsample, as well as a difference in side effect rates of 40 percent for St. John's wort as opposed to 26 percent for placebo.
The second study to refute previous claims is one done by the Hypericum Depression Trial Study Group. This group tested St. John's wort against placebo and sertraline. Strangely enough, this study found placebo to have a 31.9 percent efficacy, while St. John's wort had a 23.9 percent efficacy, and sertraline had a 24.8 percent efficacy. The study concluded that St. John's wort was ineffective for major depression, but this must be reconciled with the fact that sertraline had the same result. The study does cite that what they call established antidepressants, referring to allopathic antidepressants, fall short in about 35 percent of trials.
What these studies appear to show is that St. John's wort appears to be successful for mild to moderate depression. Furthermore, these studies assert that St. John's wort has significantly fewer incidences of side effects that common allopathic antidepressants. The latest two American studies, by Shelton et al. and the Hypericum Depression Trial Study Group, appear to show that St. John's wort may not be effective for severe depression, and are therefore not inconsistent with most of the previous research that tested it for mild to moderate depression. This conclusion actually fits with the popular philosophy that CAM therapies are not used for life-threatening medical conditions, but it still needs to be tested, given that a study in the Gaster and Holroyd meta-analysis showed that St. John's wort was effective for severe depression.
One must also consider the biases of the investigators. Many of the meta-analytic studies involved trials in Germany, where herbal remedies are more acceptable in the medical community and St. John's wort is licensed for use. In contrast, in the United States, the medical establishment has traditionally looked down upon CAM therapies. This may be the reason for the publishing of the Hypericum Depression Trial Study Group's study, even though it could be considered rather weak, given that sertraline, as an FDA approved antidepressant drug, was shown to have no effect relative to placebo.
Part of the bias of the American medical establishment stems from the fact that the active agents of St. John's wort have not been isolated. The extract from the herb "contains at least 10 substances that have been shown to have biological activity, including hypericin, pseudohypericin, xanthones, monoterpenes, b-sitosterol, quercetin, and catechin." Some of these agents have been shown to bind to neuroreceptors in the brain, as well as to prevent the uptake of neurotransmitters. Some scientists have conjectured that St. John's worse may act as a monoamine oxidase inhibitor, but this has shown not to be true at anywhere close to the extent of allopathic MAOIs.
Careful reading shows that both the Shelton et al. study and the Hypericum Depression Trial Study Group also have financial disclosures, which can show possible biases. These disclosures show that the authors have significant interests in the well being of allopathic drug companies by owning stock in them. Furthermore, many of these allopathic drug companies have funded the research of these authors.
These companies, many of which have invested millions in patents for antidepressants, include Pfizer, which manufactures sertraline under the trademark Zoloft, Eli Lilly, which manufactures fluoxetine under the trademark Prozac, Novartis, which manufactures imipramine under the trademark Tofranil, GlaxoSmithKline, which manufactures paroxetine under the trademark Paxil, Bristol-Myers Squibb, which manufactures nefazodone under the trademark Serzone, Astra Zeneca, which manufactures amitriptyline under the trademark Elavil, and Forest Pharmaceuticals, which manufactures citalopram under the trademark Celexa. Given the grant money invested in their research and the interest in the stocks of these companies, these authors would be less likely to conclude that an alternative therapy could do as well as the allopathic ones.
Future research shows numerous studies that could be undertaken with St. John's wort. Linde et al. recommend that St. John's wort be compared to allopathic antidepressants only in future studies, given that the safety and efficacy of the herb shown in existing studies removes the need for more placebo studies. More placebo research, however, could be used to determine the efficacy of St. John's wort for major depression. Kim et al. also cite that no long-term studies have been conducted with St. John's wort. Most trials have only been for four to six week periods. Research on long-term use will be helpful, not only for efficacy reasons, but also for further safety analysis.
Other research could involve the further identification of the exact agents and effects of St. John's wort. Discovery of the active agent(s) would allay much of the skepticism expressed for this herbal remedy. For mild and moderate depression, the future of St. John's wort appears very promising.
References
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Eisenberg, D.M., Davis, R.B., Ettner, S.L., Appel, S., Wilkey, S., Van Rompay, M., and Kessler, R. (1998). Trends in Alternative Medicine Use in the United States, 1990-1997: Results of a Follow-up National Survey. J. Am. Med. Assoc., 280, 1569-1575.
Fugh-Berman, A. and Cott, J.M. (1999). Dietary supplements and natural products as psychotherapeutic agents. Psychosomatic Medicine, 61, 712-728.
Gaster, B. and Holroyd, J. (2000). St. John's wort for depression. Arch. Intern. Med., 160, 152-156.
Hypericum Depression Trial Study Group (2002). Effect of Hypericum perforatum (St. John's wort) in major depressive disorder: A randomized controlled trial. J. Am. Med. Assoc., 287, 1807-1814.
Kalb, R., Trautmann-Sponsel, R.D. and Kieser, M. (2001). Efficacy and tolerability of Hypericum extract WS 5572 versus placebo in mildly to moderately depressed patients. Pharamacopsychiatry, 34, 96-103
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Linde, K., Ramirez, G., Mulrow, C.D., Pauls, A., Weidenhammer, W., Melchart, D. (1996). St. John's wort for depression-an overview and meta-analysis of randomised clinical trials. Brit. Med. J., 313, 253-258.
Shelton, R.C., Keller, M.B., Gelenberg, A., Dunner, D.L., Hirschfeld, R., Thase, M.E., Russell, J., Lydiard, R.B., Crits-Christoph, P., Gallop, R., Todd, L., Hellerstein, D., Goodnick, P., Keitner, G., Stahl, S.M., Halbreich, U0.
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