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Safety of St. John's Wort versus Antidepressant Drugs

In 1999, British researchers from the University of Exeter undertook the first systematic comparison of safety data on St. John's wort (Hypericum perforatum L., Clusiaceae) and four antidepressant drugs (Stevinson et al., 1999). In compiling the article, they utilized data from meta-analyses and reviews from the Medline database, manufacturers' clinical trials, drug monitoring studies, and spontaneous adverse effect reporting schemes. Although St. John's wort (SJW) was associated with fewer and milder side effects than the drug therapies, it was difficult to make direct comparisons due to the different forms in which data was presented. The authors concluded that SJW is "at least as safe, or possibly more safe" than conventional drug therapies. However, there is still a need for safety data on potential herb-drug interactions.

For this review article, the researchers compared SJW with the most widely prescribed drugs from the four main classes of antidepressants: fluoxetine (Prozac®), a selective serotonin reuptake inhibitor (SSRI); moclobemide, a monoamine oxidase inhibitor (MAOI); dothiepin, a tricyclic antidepressant; and mirtazapine, a newer class of drug known as a "noradrenergic and specific serotonergic antidepressant (NaSSA)." In placebo-controlled studies, 4.1 percent of people taking SJW reported side effects, compared with 19.8 percent in studies that tested the plant against an antidepressant drug. The researchers believe this difference may be due to patient expectations, which may lead people to report more side effects in trials involving a pharmaceutical drug. In clinical trials of the antidepressant drug mirtazapine, 65 percent of patients reported side effects. Safety statistics on the other three drugs were more difficult to compare because the data was presented as the percentage of patients experiencing individual side effects.

In general, SJW patients reported fewer and milder side effects and withdrew from studies less frequently compared with those taking antidepressant drugs. Problems associated with the four drugs covered a wider range of symptoms. Participants taking dothiepin and moclobemide reported the fewest side effects, while those taking fluoxetine and mirtazapine had the greatest number of complaints. The authors included tables of the incidence of side effects associated with each form of treatment and related dropout rates.

The authors' analysis includes an in-depth assessment of problems encountered while interpreting the data. One issue is that clinical studies may fail to detect rare or delayed side effects or even some common side effects, due to the studies' relatively short duration, small sample size, and focus on efficacy rather than safety. The authors also noted inconsistencies in the way safety data is collected and reported, in the terminology used to describe side effects, and in the methodologies used in different countries for tracking adverse effects in clinical studies.

The study also included data from drug monitoring studies and spontaneous reporting schemes, in which an FDA-type agency collects voluntary reports of side effects from the public or health practitioners. In SJW drug monitoring studies involving a total of 4,587 patients, the side effect rate ranged from 2 percent to 6.1 percent, and the rate of withdrawal was between 0.8 percent and 1.5 percent. In these studies, the most commonly reported side effects were gastrointestinal complaints, allergic reactions, fatigue, or restlessness. Data from spontaneous reporting schemes, collected from Europe and the World Health Organization, also revealed a low rate of side effects among people using SJW products. However, according to the authors, there are at least two major drawbacks to relying on data from spontaneous reporting schemes. The first is it can be challenging to establish a causal relationship between side effect reports and the plant in question. Secondly, people may tend to under-report problems experienced with herbal products.

The authors analyzed information related to potential overdose and drug interactions for this article as well. Currently, there is no data to suggest that SJW is dangerous in overdose. Although increased photosensitivity is often cited as a concern with this plant, there are only two documented cases of such reactions in humans. Moreover, researchers estimate that a severe phototoxic reaction would require a dose of SJW 30 to 50 times the standard daily dose. Among the four antidepressant drugs, dothiepin presented the biggest safety concern in terms of overdose.

At the time of the 1999 printing of this article, the authors reported no known interactions between SJW and pharmaceutical drugs. Since then, two letters published in the Lancet have raised the concern that SJW may interfere with the metabolism of drugs used in AIDS patients (Piscitelli et al., 2000) and heart transplant patients (Ruschitzka et al., 2000). The authors pointed out that there is a lack of information on possible interactions between SJW and psychotropic drugs, because patients taking these drugs are generally excluded from placebo-controlled studies of SJW. On the other hand, there have been no reports from clinical trials of interactions between SJW and medications for hypertension, circulatory disorders, bronchial asthma, and menopausal symptoms. The authors conclude the article with a discussion of some potentially serious drug interactions associated with conventional antidepressant drugs, including the rare but possibly life-threatening "serotonin syndrome" that may result when SSRI drugs are used in combination with other antidepressants. - Krista Morien, HRF

[Piscitelli SC, Burstein AH, Chaitt D, Alfara RM, Falloon J. Indinavir concentrations and St. John's wort. The Lancet 2000; 355: 547-548.
Ruschitzka F, Meier PJ, Turina M, Lüscher TF, Noll G. Acute heart transplant rejection due to St. John's wort. The Lancet 2000; 355: 548-549.
Stevinson C, Ernst E. Safety of Hypericum in patients with depression: a comparison with conventional antidepressants. CNS Drugs 1999; 11(2): 125-132.]

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