St. John's Worts and All.

One of every three adults regularly uses herbal supplements. This month, as part of our continuing survey of the multi-billion-dollar supplement industry, we look at the latest evidence behind two of the most popular herbs--St. John's wort and saw palmetto.

Five years ago, it was an obscure weed growing wild in North America, Europe, and Asia. Today, St. John's wort is one of the most popular "feel-good" herbal supplements. Millions take it as a "natural" way to fight depression, chase the blues, or lift themselves out of the dumps.

Food manufacturers, who know a good thing when they see it, have started adding small amounts to breakfast cereals, fruit drinks, canned soups, snack chips, and even chocolate bars.

Despite five years of scrutiny, however, the questions about St. John's wort far outweigh the answers. Most of the news since our last look ("Herbs for Nerves," October 1998) hasn't been encouraging.

What We Know

More than a dozen studies, all conducted in Europe, have found that St. John's wort relieves some of the symptoms of mild to moderate depression in about half the people who take it for at least three or four weeks.(1) That's the same success rate as prescription anti-depressants like Prozac, Zoloft, Elavil, and Tofranil. Placebos, on the other hand, appear to help about a quarter of those with depression.

What really sets St. John's wort apart is that the side effects commonly experienced with prescription antidepressants, such as a dry mouth or diminished sex drive, are milder and less frequent with the herb.

After reviewing all the evidence, the American College of Physicians-American Society of Internal Medicine told its 115,000 members last May that St. John's wort "may be effective in treating mild depression in the short term." But that conclusion was reached before the first large U.S. study found that people taking St. John's wort fared no better than those taking a placebo.

What We Don't Know

"The studies of St. John's wort done in Europe, while impressive, left many questions unanswered,' says Jacques Bradwejn, Chief of Psychiatry at the Royal Ottawa Hospital in Canada. Among them:

* Who benefits? St. John's wort has been studied almost entirely in people with mild to moderate depression. That's a persistent state of sadness, decreased energy, irritability, or other symptoms that interfere with work, sleep, eating, and activities that were once considered pleasurable. (Since depression can lead to suicide, it should be treated by a qualified health professional and not left to self-medication.)

Still unsettled is St. John's wort's effect on moderate to severe depression or on anxiety symptoms. What's more, "there is no evidence that it can elevate mood in people who are not depressed," says psychiatrist Richard Shelton of Vanderbilt University, who conducted the latest U.S. study.

* For how long does it work? The European studies lasted an average of only about 5 1/2 weeks. Just one exceeded two months. No one knows how long the benefits of St. John's wort last.

* How much of which extracts work? The European studies used 300 to 1,800 mg a day of any of 11 different formulations prepared from the St. John's wort flower, so there's no way to tell which brands work consistently in which amounts.

* How does it compare with prescription antidepressants? St. John's wort has only been tested against low doses of the older tricyclic antidepressants like Elavil and Tofranil. Researchers don't know how well St. John's wort would do in a head-to-head competition with higher doses or with the newer generation of antidepressants like Prozac or Zoloft.

Given the promising results from the European research, the National Institutes of Health (NIH) has made St. John's wort the subject of the first federally funded, large-scale trial of an herbal supplement in the U.S.

At 12 medical centers across the country, researchers are giving 336 patients with at least moderate depression one of three identical-looking preparations: 900 mg a day of the LI-160 extract of St. John's wort (available as the Kira brand), the prescription antidepressant Zoloft, or a placebo (sugar pill). Those who respond to St. John's wort during the two-month trial will take it for four more months. Results are not expected until next year.

Meanwhile, the first large-scale study of St. John's wort in the U.S. has turned up disappointing results. At Vanderbilt University and ten other medical centers, Richard Shelton and his colleagues gave 200 patients with moderate depression either 900 mg of the LI-160 extract of St. John's wort or a placebo every day for eight weeks. Those who didn't respond to the herb after four weeks were given up to 1,200 mg a day.

After eight weeks, St. John's wort was no better than a sugar pill. "Our data suggest that St. John's wort is no more effective than a placebo in patients with at least moderate depression," says Shelton. The study, funded by Pfizer (which makes Zoloft), has not been published yet.

Why might the U.S. trial have contradicted the European research?

"Some of the earlier studies in Europe were conducted in primarycare practice settings with physicians who may not have had any experience with research in depression," says Shelton. "We selected highly respected researchers here in the U.S. who were more experienced with doing a study on depression."

Interactions with Drugs

Part of St. John's wort's appeal is that it causes milder and less frequent side effects than prescription antidepressants. But that doesn't mean it's harmless. Alarming new reports suggest that the herb can interfere with prescription drugs.

St. John's wort seems to stimulate enzymes in the liver that inactivate and help remove drugs from the body. In other words, St.-John's-wort-users eliminate some drugs from their systems faster than they otherwise would. That can decrease drug levels in the blood to the point where they are too low to fight disease.

In one report earlier this year, eight healthy men and women were given a protease inhibitor called indinavir (Crixivan), which combats the HIV virus, along with St. John's wort. "The results were dramatic,' says NIH's Stephen Piscitelli.

"They all showed a marked drop in blood levels of indinavir ranging from 49 to 99 percent." That would render the drug virtually useless.(2)

In another report, when two men whose heart transplants had worked smoothly for a year began taking St. John's wort, their bodies quickly started rejecting their new hearts.(3) Apparently, the herb speeded up their bodies' normal removal of cyclosporine, the immuno-suppressant drug they were taking to prevent rejection.

Other prescription drugs that may be weakened by St. John's wort include oral contraceptives and medications used to treat heart disease, depression, seizures, and certain cancers (see "Wort's the Matter?" p. 8).

"Interactions between St. John's wort and these drugs can be dangerous," warns Piscitelli, "so it's important for patients to keep their physicians and pharmacists informed about the use of any herbal products.'

Quality Control

Supplement manufacturers continue to have problems producing high quality St. John's wort products. At least four organizations--two newspapers, a magazine, and a Web site--have analyzed dozens of brands of St. John's wort during the past two years. All four found serious deficiencies in many of the products.

In January of 2000, for example, the Boston Globe sent seven brands of St. John's wort to two labs for two different kinds of tests. Only one brand, Nature's Resource, was at least 0.3 percent hypericin, the standard amount of what may be one of the active ingredients in St. John's wort. The brands that had less: CVS, Herbalife, Natrol, NatureMade, Quanterra, and YourLife.

And only two of the brands--Quanterra and NatureMade--passed a test of the supplements' capacity to block the uptake of the chemical serotonin by animal brain cells in test tubes. (St. John's wort may work by interfering with serotonin uptake, which leaves more relaxation-inducing serotonin in the brain.)

Earlier this year, www.vitacost. com, a Web site that analyzes and sells supplements, sent eight brands of St. John's wort to an independent lab for testing. Only two, Nature's Way Standardized Extract and Natrol Mood Support, were at least 0.3 percent hypericin and 3.0 percent hyperforin (another compound that may be an active ingredient in St. John's wort). Lower levels may be ineffective. Brands that contained less hypericin or hyperforin: Nature's Answer, Nature's Herbs, Nature's Way Mood Aid with St. John's Wort, Nature's Way St. John's Wort Herbal Single, Thompson, and Twinlab Maxilife St. John's Wort and Kava.

Unapproved Food Additive

The Food and Drug Administration (FDA) has never approved St. John's wort as a food additive. Nor has the FDA or any manufacturer declared it to be Generally Recognized As Safe (GRAS). But that hasn't stopped companies like Fresh Samantha from putting St. John's wort into its "Oh, Happy Day" fruit beverage, or South Beach Beverage from lacing its SoBe "Wisdom" drink with the herb.

Earlier this year, the FDA finally started notifying manufacturers that without approval as a food additive or GRAS affirmation, St. John's wort cannot legally be added to food. So far, the companies haven't responded.

If you see a food or drink whose label or ad suggests that it can elevate your mood with St. John's wort, save your money. Most companies don't divulge how much of the herb they put in their products. Chances are, what they add is just an excuse to jack up their prices--too little to do you any good (or harm).

THE BOTTOM LINE

* Depression is a serious condition that should be treated by a qualified health professional.

* In European studies, St. John's wort seemed to help about half the people with mild to moderate depression who took it for at least three to four weeks, but the first large-scale U.S. study showed no benefits.

* St. John's wort can make many prescription medications less effective, so make sure your physician and pharmacist know if you're taking the herb.

(1) Ann. Intern. Med. 132: 743, 2000.

(2) Lancet 355: 547, 2000.

(3) Lancet 355: 548, 2000.

RELATED ARTICLE: WORT'S THE MATTER?

You don't have to know anything about how the body breaks down chemicals to understand that if you're taking a prescription drug, you don't want an herbal supplement to remove the drug from your blood before it's had a chance to do its job.

But that's just what St. John's wort appears to do with some of medicine's most powerful tools.

Let your physician know if you're using St. John's wort and taking prescription drugs. Researchers have reported that the herb lowered blood levels of most of the drugs listed below. Other medications made the list because they're metabolized and removed from the body in the same way as drugs that are affected by St. John's wort.

TYPES OF DRUGS

* Antidepressant selective serotonin reuptake inhibitors like Paxil, Prozac, and Zoloft.

* Anti-epilepsy drugs like phenytoin (Dilantin), carbamazepine (Epitol, Tegretol), and phenobarbital.

* HIV non-nucleoside reverse transcriptase inhibitors like delaviridine (Rescriptor) and nevirapine (Viramune).

* HIV-I protease inhibitors like indinavir (Crixivan), ritonavir (Norvir), and saquinavir (Invirase)?

INDIVIDUAL DRUGS

* Cyclosporine--used to keep the body from rejecting transplanted organs.

* Digoxin (Lanoxin)--used to treat heart disease.

* Theophylline--used to treat asthma.

* Warfarin (Coumadin)--an anti-clotting drug used to prevent strokes and heart attacks.

Sources: Food and Drug Administration and Health Canada.

For more information and links to the studies mentioned in this article, see www.cspinet. org/nah/sjw.html.