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Update on St. John's wort

June is the legendary birthday of John the Baptist and the month in which St. John's wort (Hypericum perforatum) blooms. Extracts from its flowers have been used for centuries as a painkiller, sedative, and treatment for anxiety and depression. Today, St. John's wort is available by prescription in Europe and over the counter in the United States. Although it is one of the most popular herbal preparations in this country, outselling standard prescription medications for depression, its effectiveness remains in doubt.

Like most plant extracts, St. John's wort contains a mixture of compounds, and its effects are probably due to some combination of these substances; the most important one is called hypericin. Like most antidepressant drugs, St. John's wort usually takes several weeks to work. How it works is not clear — possibly like the selective serotonin reuptake inhibitors (SSRIs), by preventing reabsorption of the neurotransmitter serotonin.

What the studies show

St. John's wort first attracted widespread professional attention in 1996, when a pooled analysis of 30 European clinical trials showed that it was as effective as standard antidepressant medications. In more recent research, the picture has become muddy:

• A clinical trial conducted in 2001 found no difference between St. John's wort and a placebo in 200 people who had been seriously depressed for at least two years.

• A 2002 trial found no difference between St. John's wort and the antidepressant sertraline (Zoloft), but also no difference between either of these drugs and a placebo, in patients with moderately severe major depression.

• A large study that same year including more than 300 patients with mild to moderate depression found that a hypericin extract was slightly superior to a placebo. The difference was greater in patients who were more seriously ill.

• A study published in 2004 found that 45% of people with somatoform disorder (various physical complaints without a clear physical cause) responded to St. John's wort, compared with 20% of those taking a placebo.

• Also in 2004, researchers found that St. John's wort was no more effective than a placebo in patients with social anxiety disorder (social phobia).

• Another 2004 study indicated that an extract of St. John's wort was as effective as the antidepressant paroxetine (Paxil), with fewer side effects.

• In still another study published in 2004, 135 depressed patients were given St. John's wort, fluoxetine (Prozac), or a sugar pill. After three months, St. John's wort was more effective than fluoxetine, and patients taking it were less likely to drop out of treatment. But it was statistically no more effective than the placebo. The researchers note that this is not the first time a standard antidepressant has appeared no more effective than a placebo in a clinical trial. They conclude that the evidence as a whole "continues to suggest that St. John's wort agents may offer antidepressant efficacy for some individuals with mild to moderate depression."

Two meta-analyses were published in 2004 and 2005. One, covering 18 studies, finds that it has "less effect than previously assumed." Another, covering 37 trials with about 5,000 patients, including 26 comparisons with a placebo and 14 with antidepressant drugs, finds that St. John's wort is as effective as standard antidepressants. But the researchers add that several comparisons have shown little effect and suggest that the evidence is "inconsistent and confusing."

Side effects

Some reported side effects of St. John's wort are headache, dry mouth, dizziness, stomach upset, some light sensitivity, and rashes. But these don't seem to be common or severe. In one review of clinical trials, the extract had no more side effects than a sugar pill. There's little evidence about the safety of St. John's wort in children or women who are pregnant or breast-feeding.

Drug interactions can be a problem. St. John's wort reduces the effectiveness of many drugs by enhancing the activity of liver enzymes that metabolize them. These drugs include protease inhibitors (used to treat HIV infection), cyclosporine (which prevents the rejection of transplanted tissue), some medications for heart disease, and possibly birth control pills. St. John's wort should not be mixed with selective serotonin reuptake inhibitors, because the combination can cause a serotonin syndrome — racing heart, sweating, high fever, and high blood pressure. These interactions are difficult to predict if quality control in manufacture is poor.

That is another potential problem for American users. Most clinical trials use a standard extract manufactured in Germany. The dose can vary, but averages 300 mg three times daily of an extract containing 0.12%–0.3% hypericin. In the United States, herbal medicines are not subject to FDA regulation. The contents of a preparation may vary from brand to brand and batch to batch. Commercial products may contain more or less than the amount listed on the label, and there may be contaminants. This uncertainty about the purity, potency, and consistency of St. John's wort products can only reinforce uncertainty about its effectiveness.

Last updated:	September 05, 2008