Are your supplements safe?

In 2002, 28-year-old Jennifer Rosenthal of Long Beach, California, a truck dispatcher and mother of a four-year-old, purchased some dietary supplements on the Internet to help her lose weight quickly.

She had no idea that she was buying them from a tee-shirt salesman who was importing Chinese herbs as a sideline. Three weeks into taking only half the recommended (dose, Rosenthal slipped into a coma, her liver apparently destroyed by usnic acid, an ingredient in the supplement.

Doctors were able to save Rosenthal's life with an emergency liver transplant. She now has to take 47 pills a day to keep her body from rejecting her new liver.

Seven out of every ten adults in the U.S. take vitamins, minerals, herbs, or other supplements, according to a 2002 Harris Poll. Some--calcium, folic acid, glucosamine, and saw palmetto, fro example--are beneficial. Others--soy isoflavones, ginseng, ginkgo may or may not be. And still others--ephedra, usnic acid, kava--can be dangerous.

And any supplement can do damage if you take too much or take it in the wrong combinations.

"How many supplement takers suffer adverse reactions, no one really knows," says Christine Hailer, a medical toxicologist at the University of California at San Francisco who has analyzed reports on the toxicity of ephedra for the Food and Drug Administration (FDA). (Ephedra, which has been called an "herbal fat burner," was linked to the death of Baltimore Orioles pitcher Steve Bechler last spring.)

"We really can't tell how serious the safety questions are for dietary supplements until we look at these products more carefully," says Mary Palmer, an emergency room physician and toxicologist in Alexandria, Virginia.

Palmer, Haller, and their colleagues recently analyzed nearly 500 calls about bad reactions to supplements that had been phoned in to 11 poison control centers in the U.S. in 1998. (1)

"When I started the study I thought that maybe the safety problems with supplements really were mild and that my worries were unfounded," says Palmer. "I was very surprised to see how serious the adverse reactions really were." A third of them included heart attacks, liver failure, bleeding, seizures, and death.

Prescription medications cause an estimated 100,000 deaths and 2.2 million adverse reactions each year. While the toll from supplements is nowhere near as great, it's far from trivial. For example, more than 20,000 complaints about weight-loss products containing ephedra, including scores of deaths, have been registered during the past decade.

Supplements are regulated so much more loosely than drugs that it's impossible to know how much harm they cause.

"Drugs can be sold only if companies have enough evidence to convince the FDA and panels of independent experts that they're safe and effective and that their benefits justify their risks," says Bruce Silverglade, director of legal affairs at the Center for Science in the Public Interest (publisher of Nutrition Action Heathletter).

In contrast, "The dietary supplement market is the Wild West," says Congressman Henry Waxman, a California Democrat and longtime champion of measures to protect consumers' health.

"There are no requirements that a company prove anything about either the safety or the effectiveness of its products before they go to market."

Most people don't realize that.

"About 60 percent of U.S. consumers believe that dietary supplements must be approved by a government agency like the Food and Drug Administration before they can be sold to the public," says Nancy Wong of the Harris Poll.

Not so. Congress made sure of that when it passed the Dietary Supplement Health and Education Act (DSHEA) in 1994. "DSHEA put manufacturers in the driver's seat when it comes to which supplements are sold and what claims can be made for them," notes Palmer.

Before DSHEA, if the FDA questioned a supplement's safety, the manufacturer had to prove that it was safe. "DSHEA shifted the burden of proof," says Silverglade. "With drugs, food additives, and pesticides, it's always up to the manufacturer to prove safety. But thanks to DSHEA, the FDA has to prove that supplements are dangerous.

"Because of DSHEA," says Silverglade, "the FDA has been reduced to regulating by press release."

When the agency considers a supplement unsafe, it typically issues a consumer advisory and then discourages--but doesn't prohibit--companies from continuing to sell the product. How many consumers hear about these FDA advisories? "We don't know," concedes FDA spokesperson Sebastian Cianci. "To find that out would require research we don't have the resources to do."

Bottom line: The FDA can only bark, not bite.

In late 2001, for example, the agency received reports of young adults who developed liver damage or failure soon after starting to use a weight-loss product called LipoKinetix. (It contained usnic acid, the same substance thought to have destroyed Jennifer Rosenthal's liver a year later.) hr response, the agency put out a press release advising consumers to "immediately stop use of LipoKinetix."

But the FDA didn't ban or suspend its sale. "Given the serious hazard presented by the use of your product," the agency wrote in a letter to the manufacturer, "we strongly recommend that you take prompt action to remove LipoKinetix from the market." (As it happened, the company had already suspended production because it couldn't get a steady supply of one ingredient.) Two years later, anyone can still purchase supplements that contain usnic acid on the Internet.

Consumers are protected from unsafe drugs by at least three lines of defense: The law requires manufacturers to test drugs for safety before they're sold, the FDA removes drugs from the marketplace when serious problems become evident, and manufacturers must track and disclose adverse effects, drag interactions, and other safety problems.

But against potentially unsafe dietary supplements, consumers are left to fend for themselves. Among the obstacles they face:

* No safety testing. Pharmaceutical companies have to test their drugs to make sure they don't cause cancer, interfere with reproduction, damage organs, or cause other problems greater than they solve. In contrast, "Supplement companies have no obligation to test their products for safety before they market them," points out Christine I taller of the University of California at San Francisco.

"Some companies do small studies, hut certainly not of the magnitude you would need to detect adverse effects," adds toxicologist Mary Palmer. "In many cases, there will be no information at all about a product's safety. But that doesn't mean it's safe."

"Supplement manufacturers like to say that their products are sate because they've been used for centuries in other cultures," says Haller. "But traditional use didn't mean taking capsules of herbs day filler day, so it was really different from the way we else them now." Continual exposure to concentrated extracts "probably changes the body's response to the herbs," notes Haller. "So these products might become ineffective or even have a detrimental effect."

How can an herb that has been used for centuries still be dangerous? If it causes cancer in, say, one out of every 100 people 20 years after they take it, the increased risk would never be noticed. Yet the government calls some food additives, pesticides, and drugs carcinogens if they cause cancer in one out of every million people. That's the level that animal studies on those substances are designed to detect.

Supplement manufacturers, on the other band, don't even have to understand how the body metabolizes their products. If they did, physicians would have learned long ago that St. John's weft call be life-threatening. (It can interfere with HIV drugs and immunosuppressants for transplant patients.)

And if companies had been required to thoroughly research the safety of hydroxycitrate before putting it in weight-loss supplements, they would have learned that the pharmaceutical giant Hoffmann-La Roche abandoned the compound in the 1980s because of toxicity problems.

"We dropped hydroxycitrate when we saw that it seemed to cause testicular atrophy and other toxicities in animals," said a Hoffmann-La Roche spokesperson. "We never got as far as testing it in humans."

When told about the potential problems, a spokesperson for the firm that produces one of the two most popular hydroxycitrate formulations sold in the U.S. said, "I'm really, really surprised."

"There's no incentive for supplement companies to study the safety of their products," says Palmer. "It would be nothing but trouble for them, because they have a good deal right now." If anything's going to hurt their sales, "it's going to be safety issues. So why would they go looking for trouble?"

Take usnic acid. It's produced by lichen plants, so it falls within the loose definition of a dietary supplement. You can buy it on the Internet in the form of Usnea Lichen liquid herbal extracts. (We found one corn party that sells bottles of usnic acid capsules "for experimental research use only and not for human consumption" to anyone who claims to be at legist 18 years old.)

Yet usnic acid may have destroyed the livers of at least half a dozen people in the U.S. over the past few years. Apparently that's not enough to motivate the companies that sell it--or the FDA--to investigate its toxicity.

"I don't know anyone else who's working on the toxicity of usnic acid besides me," says Nell Kaplowitz, director of the University of Southern California Research Center for Liver Diseases in Los Angeles.

* Underreported reactions. "Mild symptoms are definitely underreported to physicians and health agencies, and, as a result, there are probably many problems with supplements that am not being described," says toxicologist Christine Haller. A 2001 report by the U.S. Department of Health and Human Services estimated that only about one out of every 100 adverse reactions is reported to the FDA.

"People are somewhat embarrassed when they have a problem with a supplement that they think maybe they shouldn't have been taking, like one of the weight-loss products," says Haller. "Why tell your doctor if year doctor didn't know you were taking it?"

What's more, people may not make the connection between a bad reaction and a "natural" supplement. And even it people call the consumer complaint number that's on the product label, "manufacturers sometimes don't do anything with those complaints," says Haller.

* Troublesome interactions. "There's competition in the marketplace now to give consumers the most for their dollar by offering combinations of herbs and other ingredients," says Haller. "But combining ingredients, especially herbs, isn't a good idea, because we really don't understand a lot about how they interact."

In their analysis of calls to poison control centers in the U.S., Haller and her colleagues found that multiple-ingredient supplements were more likely than single-ingredient ones to produce severe adverse effects.

* No required warnings. "About two-thirds of the U.S. public believes that the government requires the labels of dietary supplements to include warnings about potential side effects or dangers," says Nancy Wong of the Harris Poll.

Not so. Unlike drug labels, supplement labels don't have to disclose who shouldn't take the product, what drugs if shouldn't be taken with, or other warnings.

So, for example, beta-carotene supplements are unlikely to warn smokers that high doses (at least 25 mg, or 42.000 IU) may increase their risk of lung cancer. And zinc supplement labels are unlikely to disclose that too much zinc can compromise the immune system.

* Unreported problems. "The FDA maintains surveillance of prescription drugs by requiring prompt reports from manufacturers of all adverse events brought to their attention," says Arthur Grollman, chair of pharmacology at the State University of New York at Stony Brook.

"But there is no mandatory requirement for manufacturers of supplements to record, investigate, or forward to the FDA reports of adverse effects they might receive," he adds. "Under current regulations, there is no penalty for withholding these reports." Grollman wants Congress to require companies to report safety problems.

For years, Metabolife, the leading manufacturer of weight-loss pills that contain ephedra, denied that it knew of any serious complaints about its products. Then last year, lawyers who were suing the company all behalf of injured consumers learned that Metabolife had, in fact, received more than 13,000 complaints from users.

Among them were more than 1,000 reports of significant adverse reactions, including 18 heart attacks, 26 strokes, 43 seizures, and five deaths)

An angry FDA has asked the Department of Justice to pursue filing criminal charges against Metabolife officials for lying to the agency.

* Unavailable adverse reaction reports. For years, the Food and Drug Administration has been collecting reports of adverse reactions to dietary supplements. But last year the agency pulled the database from its Web site, saying that the information was confusing.

Last June, the FDA installed a new system (the Center for Food Safety and Applied Nutrition Adverse Events Reporting System, or CAERS) to track complaints by consumers and physicians to its MedWatch hotline (800-FDA-1088 or www.fda.gov/medwatch/report/consumer/consumer.htm).

But health professionals and the public can't view the complaints that have been submitted to CAERS.

"We're working on a way to give the public access to this information, but that's at least a year away," says FDA spokesperson Sebastian Cianci. "Until then, you need to file a Freedom of Information Act [FOIA] request to see the information."

That can take months, which is tar too king to help people track down what's causing a reaction. And it certainly would have been too long for people like Jennifer Rosenthal, the California mother who paid a steep price for her lesson in supplement safety.

The Top Ten Supplements: How Safe?

How safe are the 10 most popular herbal supplements? Here's what you
need to know. Just keep in mind that most reactions are rare; in some
cases they're based on just one or two reports from physicians. Until
more research is done, it's probably wise for children and pregnant or
nursing women not to take any of these supplements.

Supplement        What Consumers              Reported
                  Expect                      Reactions

Black Cohosh      To relieve symptoms of      Mild gastrointestinal
                  menopause.                  distress.

Cranberry         To prevent or treat         Regular use of cranberry
                  urinary tract infections.   concentrate tablets
                                              might increase the risk
                                              of kidney stones.

Echinacea         To prevent or treat         Minor gastrointestinal
                  colds or other              symptoms. Increased
                  infections.                 urination. Allergic
                                              reactions.

Garlic            To lower cholesterol        Unpleasant breath
                  levels.                     odor. Heartburn and
                                              flatulence.

Ginkgo Biloba     To improve memory.          Mild headache. Upset
                                              stomach. Seizures
                                              (possibly caused by
                                              contamination with
                                              ginkgo seeds, which
                                              are toxic).

Ginseng           To increase energy and      Insomnia. Menstrual
                  relieve stress.             abnormalities and
                                              breast tenderness with
                                              long-term use.

Saw Palmetto      To prevent or relieve       Mild gastrointestinal
                  the symptoms of an          distress.
                  enlarged prostate.

Soy Isoflavones   To relieve menopausal       None reported.
                  symptoms, prevent
                  breast or prostate
                  cancer, and strengthen
                  bones.

St. John's Wort   To alleviate                Mild gastrointestinal
                  depression.                 distress. Rash.
                                              Tiredness. Restlessness.

Valerian          To induce sleep or          May impair attention
                  relaxation.                 for a few hours.

Supplement        Who Should be               May Interact With
                  Especially Careful

Black Cohosh      Women who have had          No drug interactions
                  breast cancer (in an        known.
                  animal study, black
                  cohosh caused cancer to
                  spread).

Cranberry         People susceptible to       Antidepressants and
                  kidney stones.              prescription painkillers.

Echinacea         People with autoimmune      No drug interactions
                  diseases (like multiple     known.
                  sclerosis, lupus, and
                  rheumatoid arthritis).
                  May also trigger
                  episodes of erythema
                  nodosum, an inflammation
                  that produces tender
                  nodules under the skin.

Garlic            People who are about to     Blood-thinning drugs
                  have--or have just          like Coumadin
                  had--surgery (garlic        (warfarin), heparin, or
                  thins the blood). Women     aspirin. Blood-thinning
                  just before or after        supplements like ginkgo
                  labor or delivery.          or high doses of vitamin
                                              E. Chloroxazone, which
                                              is used to treat painful
                                              muscle conditions. HIV
                                              drug.

Ginkgo Biloba     People with bleeding        Blood-thinning drugs
                  disorders like              like Coumadin (warfarin),
                  hemophilia. People who      heparin, or aspirin.
                  are about to have--or       Blood-thinning
                  have just had--surgery.     supplements like high
                  Women just before or        doses of vitamin E. The
                  after labor or delivery.    antidepressant trazodone.
                  People with diabetes.       Anti-diabetes drugs.
                                              Thiazide diuretics.

Ginseng           Women who have had          Any drug metabolized by
                  breast cancer (ginseng      the enzyme CYP 3A4 (ask
                  stimulated the growth of    your physician). MAO
                  breast cancer cells in      inhibitor drugs or
                  test tubes). People with    digitalis. May increase
                  high blood pressure who     the activity of insulin
                  aren't taking medication    and oral hypoglycemics
                  to lower it.                and decrease the
                                              activity of Coumadin
                                              (warfarin) and
                                              ticlopidine.

Saw Palmetto      People with bleeding        Blood-thinning drugs
                  disorders like              like Coumadin (warfarin),
                  hemophilia. People who      heparin, or aspirin.
                  are about to have--or       Blood-thinning
                  have just had--surgery.     supplements like ginkgo
                                              or high doses of vitamin
                                              E.

Soy Isoflavones   Women who have had--or      No drug interactions
                  are at high risk            known.
                  for--breast cancer (soy
                  isoflavones may increase
                  cell proliferation).
                  Pregnant women. People
                  with impaired thyroid
                  function.

St. John's Wort   People with skin that's     Ritalin, ephedrine
                  sensitive to sunlight.      (found in ephedra), and
                  People taking UV            caffeine. May increase
                  treatment. People with      the activity of protease
                  bipolar disorder.           inhibitors (for HIV),
                                              digitalis (for heart
                                              disease), statin drugs
                                              (for high cholesterol),
                                              warfarin
                                              (blood-thinner),
                                              chemotherapy drugs,
                                              oral contraceptives,
                                              tricyclic
                                              antidepressants,
                                              olanzapine and clozapine
                                              (for schizophrenia), and
                                              theophylline (for
                                              asthma). May increase
                                              sensitivity to sunlight
                                              if  combined with sulfa
                                              drugs, Feldene
                                              (anti-inflammatory), or
                                              Prilosec or Prevacid
                                              (for acid reflux).

Valerian          People about to operate     May increase the activity
                  heavy machinery or drive.   of central-nervous-system
                                              depressants like
                                              barbiturates (such as
                                              Seconal) and
                                              benzodiazepines (such as
                                              Valium or Halcion).

Sources: The Natural Pharmacist, Healthnotes, and CSPI.

(1) Lancet 361: 101, 2003.

(2) Department of Health and Human Services, Office of the Inspector General: Adverse Event Repairing for Dietary Supplements, An Inadequate Safety Valve. OEI-01-00180, April 2001.

(3) Government Accounting Office: Dietary Supplements Containing Ephedra. GAO-03-10421, July 2003.

CASE STUDY

In 1995, 34-year-old Rosalie Talbert of Anchorage, Alaska, a working mother of four, suffered a stroke at a company picnic. She had been taking a weight-loss product containing caffeine and the herb ephedra on-and-off for three years. After missing six months of work to recuperate, she still had occasional hand tremors. A jury awarded her $13.3 million in damages, the first against a company selling ephedra. Several hundred more ephedra lawsuits are in the pipeline.

CASE STUDY

In 2001, a healthy 45-year-old woman (she was never named in public documents) began feeling nauseated and weak. For about two months, she had been taking kava, which is marketed as a stress reliever. A week later, she was hospitalized with jaundice and hepatitis. Eventually she became the 11th kava taker in Europe and the U.S. who needed a liver transplant. The cases helped persuade the governments of Canada, the United Kingdom, Germany, Switzerland, and France--but not the United States--to restrict or ban the sale of kava.

EIGHT TO AVOID

Despite evidence that these eight products can cause serious problems, most are still available, either over the counter or via the Internet.

* Aristolochic acid. The ingredient in some traditional Chinese medicines is toxic to the kidneys.

* Chaparral. In 1992, the FDA advised consumers to "stop taking chaparral immediately" because it can cause hepatitis.

* Comfrey. It can cause chronic liver disease.

* Ephedra. It has been linked to high blood pressure, strokes, and heart attacks and is 200 times more likely to cause an adverse reaction than all other herbs combined.

* Kava. It's a suspect in liver damage that has resulted in 11 liver transplants over the last several years.

* PC SPES and SPES. These supplements, which held promise as prostate-cancer fighters, turned out to be frauds. They worked like hormones only because they were spiked with hormones, a blood thinner, an antiinflammatory, and several other drugs.

* Tiratricol. In 2000, the FDA warned consumers not to use weight-loss supplements containing this thyroid hormone, which can cause strokes and heart attacks.

* Usnic acid. This "natural" compound (it's found in lichen), which is used in some herbal mixtures, appears to be toxic to the liver.

Sources: Food and Drug Administration (www.cfsan.fda.qov/%Edms/ds-warn.html) and CSPI.

www.Is-My-Herb-Safe.com

The Internet is crawling with information on dietary supplements. Most of it is designed to sell you something. Here are two of the best sites for reliable information and one site that you shouldn't trust.

* The Good. The Natural Pharmacist (TNP) offers detailed, readable, generally reliable information about the uses and the safety of nearly 500 dietary supplements. TNP is prepared by physicians and pharmacists at Healthgate Data Corporation of Burlington, Massachusetts, which supplies medical information to hospitals and pharmaceutical and health insurance firms. The Natural Pharmacist is available free at the online supplement vendor www.iherb.com and to subscribers of www.ConsumerLab.com, a site that tests whether supplements contain what their labels claim.

* The Less Objective. Healthnotes' short summaries of more than 700 supplements appear on touchscreen kiosks in more than 6,500 pharmacies, supermarkets, health food stores, and vitamin shops in the U.S., Canada, and the United Kingdom. They're also a popular feature on Web sites that sell supplements. In general, Healthnotes' descriptions are shorter, less objective, and more superficial than The Natural Pharmacist's. Maybe that's because the service is designed to be "a powerful selling tool" for stores to "drive sales" and build "healthy profits," according to the company. Healthnotes is available free at dozens of sites, including www.gnc.com and www.drugstore.com.

* The Ugly. Intramedicine, Inc., provides a short encyclopedia of information on close to 200 dietary supplements for the Web site of the Dietary Supplement Education Alliance (DSEA), an industry coalition that claims to promote the responsible use of supplements. The DSEA Web site portrays a fantasy world where all supplements have proven benefits, all side effects are manageable, and no supplements are poorly made. Intramedicine overlooks important scientific research, presents hypotheses as facts, relies on 30- and 40-year-old weak studies to justify unusual uses for supplements, and ignores important safety information about beta-carotene and other supplements. Intramedicine is available at www.supplementinfo.org.

Smaller Useful Sites

* The FDA's Warnings and Safety Information and Dietary Supplements site lists the supplements that the FDA advises consumers not to use. (www.cfsan.fda.gov/%7Edms/ds-warn.html)

* The National Institutes of Health's Office of Dietary Supplements provides links to fact sheets on two dozen supplements, including garlic, vitamin A, and St. John's wort. Missing are ginkgo, chromium, kava, and many others. The fact sheets are written by different government agencies, so the quality and detail vary. (dietary-supplements.info.nih.gov/showpage.aspx?pageid=90)

* The U.S. Army Center for Health Promotion and Preventive Medicine provides fact sheets on a handful of supplements. (chppm-www.apgea.army.mil/dhpw/Wellness/dietary/factsheets.aspx)

* Memorial Sloan-Kettering's Integrative Medicine Service has brief information on the effectiveness and safety of more than 100 supplements, mostly to inform cancer patients about potential interactions with their treatments. (www.mskcc.org/mskcc/html/11570.cfm)