The L.A. Times front-page
story on St. John's Wort
Monday, August 31, 1998
Remedy's U.S. Sales Zoom, but Quality Control Lags
St. John's wort: Regulatory vacuum leaves doubt about potency, effects of herb used for depression.
By TERENCE MONMANEY, Times Medical Writer
It is the fastest-growing "alternative" in a nation increasingly enchanted with unconventional and unproven treatments. A million or more Americans have lately tried St. John's wort, an herbal remedy for depression with 1998 retail sales estimated at $400 million--up 3,900% since 1995.
Already the leading antidepressant in Germany, where clinical studies have suggested it can ease mild or moderate depression, it cannonballed onto the American self-help scene last year after being hailed as "nature's Prozac."
But independent laboratory tests commissioned by The Times raise questions about whether consumers are getting what they pay for. Three of the 10 brands of St. John's wort tested--including a brand from the nation's leading supplement distributor--had no more than about half the potency listed on the label. Four more had less than 90% of the indicated potency, according to the laboratory.
A Cautionary Perspective
If the basic findings are representative of the dozens of St. John's wort supplements now on the U.S. market, it would suggest that Americans are spending millions of dollars on products that do not live up to their claims, health experts say.
Moreover, a significant number of depressed people may be laying hopes on products too weak to help them even when taken at the recommended dosages, medical researchers say.
"How is it possible to appropriately regulate a treatment regimen if you can't even be sure of the dosage?" said Dr. Norman Rosenthal, a research psychiatrist at the National Institute of Mental Health and a strong believer in St. John's wort's mood-elevating properties.
"You're using this [product] for important reasons and you want to know you're getting what you're supposed to be getting," he said after reviewing results. "It's quite important that there should be truth in advertising."
Issues raised by the Times-commissioned study offer a cautionary perspective on the booming U.S. herbal market. Sales of St. John's wort and other formerly exotic botanical remedies, including ginseng, ginkgo biloba, echinacea and saw palmetto, may reach $4.3 billion this year, according to Nutrition Business Journal.
One source of concern is that, unlike pharmaceutical drugs, herbal supplements do not undergo government scrutiny before marketing.
The Food and Drug Administration can seize dietary supplements that turn out to be harmful, fraudulent or improperly promoted. But lax pre-market government oversight means that consumers have less than the assurance of product quality they expect of medications, said Sally Guthrie, a University of Michigan pharmacy professor.
People taking St. John's wort cannot "be assured from batch to batch and manufacturer to manufacturer that they're getting the same quality or amount," she said.
The Times commissioned the St. John's wort analysis--among the first to be published--to check the consistency of retail products. For the analysis, 10 pills were sampled from each of three containers of one lot of each product. Each product was identified only with a code, so the laboratory would not know the brand being tested.
Such a limited sampling is not designed to support broad conclusions about the quality of any particular product. But experts say it is sufficient to highlight questions that many researchers and herb industry officials have raised about the reliability of St. John's wort supplements.
In the test, one of the lowest-scoring products sampled, with about 20% of the labeled potency, was from Sundown Herbals, a division of Rexall, the nation's No. 1 distributor of dietary supplements.
Informed of the results, Deborah Shur Trinker, Sundown's vice president of regulatory affairs, said they were "false" and "misleading."
Trinker, in a letter to The Times, argued that the tests involved too few pills for the findings to be significant. Trinker also argued that chemical ingredients specific to Sundown's brand might interfere with the analysis, giving an artificially low reading. Finally, she stated that an independent lab hired by Sundown had found the product to be 100% potent.
However, The Times arranged for a second lab to analyze the capsules. That lab's findings were consistent with The Times' original results.
Two of the other low-scoring companies, Pure Source and Futurebiotics, declined to comment on the results.
No Standards Established
The herbal industry currently gauges the potency of St. John's wort by measuring the concentration of a family of compounds in the herb known collectively as hypericin. The lab commissioned by The Times, Flora Research of San Juan Capistrano, used the hypericin-measuring method adopted by health authorities in Germany, who have extensive experience analyzing and regulating St. John's wort.
Five independent experts who reviewed The Times' procedures said the approach was sound. "The analysis method used is the best one widely available," said John Fitzloff, director of the analytical chemistry laboratory at the University of Illinois in Chicago and an authority on botanical testing.
However arcane the controversy over testing methods, it is related to St. John's wort product consistency--and thus consumer confidence. There are "no officially established standards of quality" for the herb in the United States, according to the U.S. Pharmacopeia, an independent organization that sets drug safety and purity standards.
"Although some companies may test their own products," it stated this month in a report on the herb, "the quality of other products that are for sale cannot be guaranteed."
Not all companies challenged The Times' tests. Within hours of being informed of the results, for example, officials of Trader Joe's, the Southern California market chain, said they would remove the particular St. John's wort lot tested from store shelves.
"Our customers have an expectation that what is on the label is inside the bottle," said marketing vice president Pat St. John.
Another vital issue that surfaced in The Times' product survey pertains to safety information.
Three of the 10 products sampled provided no safety information on the label, even though St. John's wort can have side effects.
The most frequently noted possible side effect is light sensitivity. Ranging cattle that feed on the plant have been known to get blisters on their hide and die of overexposure to the sun. In some clinical experiments, fair-skinned people in particular got sunburns after taking twice the usual amount of St. John's wort.
Anecdotally, World Wide Web bulletin boards discussing the herb are riddled with messages blaming it for unexpected sunburns. European health authorities and U.S. scientific bodies have issued clear warnings about the problem.
Similarly, health authorities have cautioned pregnant women against taking the product. The European Scientific Cooperative on Phytotherapy said in a 1996 report that "the product should not be used in pregnancy and lactation without medical advice."
The U.S. Pharmacopeia says that there have been no reports of adverse effects on fertility or of birth defects associated with St. John's wort use, but the herb "should be avoided by pregnant women because of a lack of published safety data."
Evidence that in ancient times the herb was used to induce abortions should also give pregnant women pause, according to John Riddle, a historian at North Carolina State University.
Combing ancient medical texts, Riddle found that the herb has been part of folk medicine for 3,000 years.
In addition to being a treatment for "melancholia"--first recorded 1,100 years ago, Riddle found--St. John's wort was also used for abortions.
Package labels should plainly state that pregnant women should not take this herbal product "simply out of historical prudence," he said at a conference this spring of the American Herbal Products Assn.
Another labeling issue concerns young children, who are increasingly being given St. John's wort supplements or tinctures, to judge from Internet messages by parents seeking dosage advice.
In The Times' test, eight of the 10 brands did not warn parents against giving the product to young children. And yet, the new U.S. Pharmacopeia report said, "use of hypericum in children should be avoided because of the lack of safety data."
Wide-Open Market in U.S.
Though there are gaps in the evidence for the herb's safety, many scientists and physicians cite the experience in Germany, where millions of people have taken the herb over the last decade without apparent excessive adverse effects.
But Germans and Americans are taking St. John's wort in very different environments. There, the herb is considered a drug. Manufacturers must register their products with the government and adhere to strict premarketing quality standards. Doctors prescribe it and health plans cover it. And most patients take the herb under a doctor's care.
Here, the herbal market is wide open. Most Americans who use St. John's wort, experts say, are doing so without their doctors' advice and in many cases they are hiding their use.
The American Psychiatric Assn. sharply criticized the practice. "No one who thinks he or she may be depressed should self-medicate with St. John's wort or any other 'alternative' remedy," it said in a statement last March.
For one thing, symptoms of depression could actually be a sign of serious physical disease. Also, proven antidepressant medications are available.
The appeal of herbal remedies to Americans is obvious. Promoters describe them as safe, gentle, inexpensive and "natural" alternatives to pharmaceutical drugs and other harsh medical treatments. Consumers buy them without a prescription, forgoing the costs and hassles of doctor visits and managed-care bureaucracies.
A part of the rationale for taking herbal remedies is sound. After all, many drugs have been derived from plants, whether old-fashioned opium or modern-day taxol, a compound used to treat breast cancer that is derived from the Pacific yew tree. As many as 120 drugs currently used by physicians reportedly have plant origins, according to a University of Illinois study.
A resurgence of interest in natural remedies is at the core of the alternative medicine movement, said Dr. Harold Bloomfield, a La Jolla psychiatrist and an author of two books touting the benefits of St. John's wort. Bloomfield's appearance on the TV program "20/20" last year is widely cited as one of the sparks that ignited the current boom.
Still, he said, "good pharmacological studies are needed so a physician can feel a sense of confidence and safety prescribing" St. John's wort.
The explosion of interest in St. John's wort also testifies to depression's huge, often hidden toll.
About 17 million adults suffer from serious depression. And tens of millions more are said by researchers to endure a milder, less persistent form of the disorder called "subsyndromal" depression or "dysthymia."
To some mental health professionals, St. John's wort--the first over-the-counter product said to have antidepressant properties--represents a new opportunity to ease the suffering of millions. That is especially important because approximately two out of three depressed people do not seek any help for the condition, according to government studies.
"For the depressed person who would previously not have sought medical help, perhaps for financial reasons or out of feelings of shame or the fear of stigma, St. John's wort might well be a boon," Rosenthal, of the Mental Health Institute, writes in his new book "St. John's Wort: The Herbal Way to Feeling Good."
Clinical Evidence of Effectiveness
The clinical evidence on the effectiveness of St. John's wort appears positive overall, according to independent summaries of the data. So far, 27 published clinical studies of 2,291 patients have met strict scientific criteria, such as randomly assigning patients to a treatment or control group, according to a new overview by Dr. Klaus Linde of the Technical University in Munich, Germany, and Dr. Cynthia Mulrow of the Veterans Affairs Medical Center in San Antonio.
Pooling the data from those studies, Linde and Mulrow found that 56% of the patients felt less depressed a month or longer after taking St. John's wort, compared with 25% of the patients who were given a placebo.
But in their analysis--the most comprehensive review of the evidence so far--the medical researchers described several key weaknesses in the existing studies, all of which were conducted in Europe or the United Kingdom.
For instance, most of the trials were too brief, lasting only four weeks, whereas the usual minimum for studying antidepressant drugs is six weeks.
Moreover, none of the published studies so far compares St. John's wort with the newest antidepressant drugs, such as Prozac and Zoloft.
Mulrow also said there was reason to believe that some negative clinical findings had been suppressed. That could stem from what researchers call "publication bias"--the tendency of scientists not to bother reporting unimpressive findings, fearing that medical journals would not be interested in a "failed" study. A more pernicious bias occurs when a study's director or sponsor withholds negative data.
An expert committee of the German government's drug-regulating branch concluded 14 years ago that St. John's wort could reasonably be prescribed for "depressive moods, anxiety and/or nervous unrest."
But the U.S. Pharmacopeia, citing a "lack of adequate scientific evidence" on the effectiveness of St. John's wort, said its expert panel could not support "a general recommendation for its use."
To bridge the gulf between U.S. questions and European acceptance, two large U.S. studies are getting underway. One, led by Dr. Richard Shelton, a research psychiatrist at Vanderbilt University Medical Center, is funded by Pfizer, which makes the antidepressant drug Zoloft. The other study, with $4 million from the National Institutes of Health, is being coordinated by Dr. Jonathan Davidson, a research psychiatrist at Duke University.
Both studies will involve people with serious depression, to put the herb to a stricter test than older studies have done. The subjects will receive St. John's wort, an antidepressant drug or a placebo for at least eight weeks and as long as six months. Results are expected in two to three years, the researchers say.
Factors in Potential Quality Problems
Of course, even if St. John's wort is eventually proved effective, it would not help consumers who happen to buy a product lacking potency, health researchers and herb industry officials say.
Several factors contribute to potential quality problems with St. John's wort extracts, experts say. Greatly increased demand for the herb, coupled with tight supplies, has quadrupled the wholesale price of raw plant material in the last three years. Processing and extracting methods are onerous. Moreover, scientists have not identified all the active ingredients.
In the face of rocketing demand, unscrupulous manufacturers have reportedly turned to fraud. Some of the St. John's wort material on the wholesale market has been identified as coming from a different, perhaps less active, species of the plant, according to some distributors. And the most common tests of St. John's wort potency can be fooled by adding synthetic chemicals to the mixture, making poor extracts appear up to grade, said Joerg Gruenwald, head of the German herbal medication company PhytoPharm Consulting.
"We have heard that people are doing that," he said.
None of the products sampled by The Times, however, showed evidence of fraud, according to an analysis that checked for chemical adulterants and also verified that the extract came from the correct plant species.
Also contributing to quality control questions is the leeway U.S. herbal distributors have to copy one another's products, which are very seldom patented, since herbal remedies are generally based on centuries of use.
Copycat herbal supplements are a concern because they may not in fact be identical to the original formulations tested in research studies, said Mark Blumenthal, director of the American Botanical Council, an independent scientific and policy group, which receives some funding from the herb industry.
"Is it possible that some of the herbal supplements out there are not wearing any clothes?" he said. "Are they just making claims . . . after borrowing somebody else's research conducted on a different commercial product that may or may not be similar?"
Industry Trying to Police Itself
Given the absence of direct government oversight, the herb industry is taking steps to improve standards and police itself. Industrial Laboratories, a Denver-based testing firm, has formed the Institute for Nutraceutical Advancement, an industry-funded group to validate methods of analyzing botanical products.
The National Nutritional Foods Assn., a trade group, randomly tests members' herbal supplements to encourage adherence to label claims. In a recent spot check of 45 retail St. John's wort supplements, the group found that only four contained less than 100% of labeled potency.
Meanwhile, herb distributors have also uncovered potency problems. Last year, Botanicals International of Long Beach teamed with a German firm to test wholesale St. John's wort extracts. Using the same method employed by the Times-commissioned lab, only one out of the 10 extracts analyzed was as potent as the wholesalers had maintained, said Chris Tower, a product manager at the company.
Consumers face a daunting task, he said: "You can walk into a store and if you're not up to speed it can be darned confusing . . . trying to make an educated guess about what is quality and what is not."
The analysis of St. John's wort commissioned by The Times examined whether retail products were as potent as they claimed to be. The analytical technique, called spectrophotometry, tested each product for a family of compounds known collectively as hypericin.
Scientists say that hypericin is not the only, and probably not even the primary, ingredient with antidepressant activity in St. John's wort. The herb contains several other compounds that also appear to affect brain chemistry in ways that could lift mood, according to test-tube studies of nerve cells. Strictly speaking, then, a product with low hypericin levels is not necessarily an inactive one, researchers and herbalists say.
However, unusually low hypericin levels are generally accepted in the industry as a sign of poor quality. Hypericin remains the gauge of authenticity, purity and strength of St. John's wort extracts.
For the tests, only products that specified the hypericin level were sampled. Bought in six Los Angeles-area stores in July, they were labeled as "standardized" or having "certified potency," "high potency" or "guaranteed potency."
Overall, seven of the 10 products contained between 75% and 135% of the labeled hypericin level, and three contained no more than about half the labeled potency, the lab found.
Cost and potency did not necessarily go together. Two of the three lowest-scoring brands cost less than the average price of 18 cents per pill. But two of the three highest-scoring brands also cost somewhat less than the average. The most expensive brand was among the highest in potency, but the second-most expensive brand was among the least potent.
Some of the variation in potency may reflect natural decay of hypericin in the product after it leaves the factory, several scientists said. For instance, one of the three packages of Kira--the brand used in most of the German clinical trials--was found to have pills with 81% of the labeled hypericin level, whereas the other two packages had 91%. Dick Middleton, technical manager of Lichtwer Pharma in Britain, said the lower-level package might have suffered in shipping and storage since leaving Berlin some months before.
Three methods exist for measuring hypericin. The U.S. Pharmacopeia plans to issue specifications for a new hypericin test this fall. The method used in the tests for The Times is a spectrophotometric test--a measurement of color in a solution--called DAC-91.
Officials of several companies objected to the use of that method, saying it yields results that are slightly lower than an earlier version, called DAC-86. Some of the companies still use DAC-86 to monitor their products.
The head of Jarrow Formulas, Jarrow Rogovin, for example, said the method used in The Times' survey resulted in hypericin readings that are 20% below those found by the method the company's extract supplier uses, "which accounts for the difference between our label claim and the results obtained."
Officials at Enzymatic Therapy and Nature's Resource made a similar argument.
The method used by The Times is "the accepted industry standard for testing," said Roy Upton, an herbalist and editor of the American Herbal Pharmacopoeia. It was adopted several years ago by the German government for St. John's wort testing, though methods continue to evolve.
Just how closely herbal supplements should adhere to their labeled potency is a matter of some debate. FDA regulations state that the concentration of labeled ingredients in dietary supplements, including herbal medications, must equal 100% of the amount claimed on the package throughout the product's shelf life.
In reality, though, holding herbal products to that standard can be difficult because the chemical composition of a plant varies from crop to crop, and analytical techniques for measuring key compounds can yield somewhat different results, an FDA official said.
So some experts argue that herbal products containing 80% to 120% of the labeled potency are close enough. "That might be reasonable," said Sally Guthrie, a University of Michigan clinical pharmacist.
Others narrow the margin to 90% to 110%. "At this point, 90% of label claim is what I would specify" as a minimum, said V. Srini Srinivasan, a senior scientist at the U.S. Pharmacopeia.
But Mark Blumenthal, director of the American Botanical Council, an independent scientific and policy group, disagrees, arguing that a product really should have 100% of what its label claims.
"If they say they have 0.3% hypericin at 300 milligrams, they should have that," he said. "As a consumer, I want to know that I'm getting what I pay for."
Testing St. John's Wort
In a spot check of retail St. John's wort supplements, the potency varied, according to an independent laboratory test commissioned by The Times. The potency depends on the milligrams of the compound hypericin in each capsule or tablet.
The tested potency represents the average of three samples. The margin of error is approximately +/- 5%. The testing, using a spectrophotometric method known officially as DAC-91, was done by Flora Research, an analytical firm in San Juan Capistrano.
Monday, August 31, 1998SAMe
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