Killing Us Softly

by Dr Paul Offit

  The possibility of harm caused by natural products sold in health food stores isn’t theoretical. Blue cohosh can cause heart failure; nutmeg can cause hallucinations; comfrey, kava, chaparral, Crotalaria, Senecio, jin bu huan, Usnea lichen, and valerian can cause hepatitis; monkshood and plantain can cause heart arrhythmias; wormwood can cause seizures; stevia leaves can decrease fertility; concentrated green tea extracts can damage the liver; milkweed seed oil and bitter orange (Citrus aurantium) can cause heart damage; thujone can cause neurological damage; and concentrated garlic can cause bleeding. Indeed, one of the worst dietary supplement disasters in history occurred in 1992, when about a hundred people developed kidney failure from a “slimming” mixture found to contain the plant aristolochia; at least seventy patients required kidney transplants or dialysis, and many later developed bladder cancers. In 2008, more than two hundred people—including a four-year-old—were poisoned by massive doses of selenium contained in Total Body Formula and Total Body Mega. The products were supposed to contain 200 micrograms of selenium per serving; instead they contained 40,800 micrograms. Herbal remedies can also cause harm: two infants died from a tea containing pennyroyal and another from a decongestant containing capsaicin. Because the dietary supplement industry is unregulated, only 170 (0.3 percent) of the 51,000 new products brought to market since the 1994 Supplement Act have documented safety tests.

  And it’s not just the supplements themselves that might be harmful, but what’s contaminating them. In 2004, researchers at Harvard Medical School tested Indian (Ayurvedic) remedies obtained from shops near Boston’s City Hall. They found that 20 percent contained potentially harmful levels of lead, mercury, and arsenic. Between 1978 and 2004, herbal medicines caused fifty-five cases of severe or fatal heavy-metal poisoning. In late 2009, Kirkman Labs, a supplement manufacturer popular among parents of children with autism, recalled fifteen thousand bottles of zinc because they contained undeclared antimony, a heavy metal.

  These problems aren’t rare. Between 1983 and 2004, poison-control centers in the United States received 1.3 million reports of adverse reactions to vitamins, minerals, and dietary supplements, of which 175,268 required treatment in hospitals and 139 resulted in death. In 2012, the FDA estimated that approximately 50,000 adverse reactions to supplements occurred every year.

  Worst of all: most people don’t realize what’s happened. A Harris poll found that 68 percent believe that the government requires herbal manufacturers to report side effects, 58 percent believe that the FDA must approve herbal products before sale, and 55 percent believe that manufacturers of vitamins, minerals, and dietary supplements cannot make claims about safety or effectiveness without scientific evidence. All these beliefs couldn’t be further from the truth. Serious problems caused by dietary supplements are the industry’s dirty little secret. Because of the Supplement Act, they’ll remain a secret.

  In 2007, as problems with the industry continued to mount, FDA regulators were finally granted permission to supervise the way supplements were made. Although they still couldn’t force manufacturers to prove that their products were safe or effective, at least they could make sure the product contained what the label said it contained. What the FDA found was appalling. Of the 450 supplement manufacturers inspected, at least half had significant problems. One, ATF Fitness, substituted ingredients without changing the product label. Others didn’t even have recipes for their products. And some manufactured products in buildings contaminated with rodent feces and urine—in one facility a rodent was found cut in half next to a scoop. “It’s downright scary,” said Daniel Fabricant, head of the FDA’s Division of Dietary Supplement Programs. “At least half of the industry is failing on its face.” Cara Welch, a vice president for the National Products Association, an industry trade group, called the findings “unfortunate.”

  In 1994, when the Supplement Act passed, sales of dietary supplements were $4 billion a year; by 2007, $28 billion; by 2012, $34 billion. America’s Magical Miracle Medicine Show is back in business.

  European regulation of the supplement industry parallels that in the United States. In Europe, drugs are regulated by the European Agency for the Evaluation of Medicinal Products (EMEA). Like the FDA, the EMEA holds drugs to a high standard of safety and efficacy before licensure. But the EMEA doesn’t regulate vitamins, minerals, dietary supplements, and herbs. Rather, regulation falls to the European Food Safety Authority (EFSA), which has a much lower bar. Lax regulation by the United States and Europe of dietary supplements isn’t the only problem. All countries have to be concerned about the illegal sale of counterfeit vitamins, nutrients, and supplements over the internet.

  4

  Fifty-One Thousand New Supplements: Which Ones Work?

  There cannot be two kinds of medicine. There is only medicine that has been adequately tested and medicine that has not.

  —Marcia Angell, former editor-in-chief of the New England Journal of Medicine

  Health food stores are a wonderland of promise. If people want to burn fat, detoxify livers, shrink prostates, avoid colds, stimulate brains, boost energy, reduce stress, enhance immunity, prevent cancer, extend lives, enliven sex, or eliminate pain, all they have to do is walk in. The question, however, is which products work? And how do we know they work?

  Fortunately, thanks to James Lind, we can figure it out. When Lind climbed aboard the HMS Salisbury—intent on finding a cure for scurvy—he moved medicine from a faith-based system to an evidence-based system. No longer do we have to believe in treatments. Now we can test them to see whether they work. For example, alternative healers recommend ginkgo or rose and orange oils for memory; graviola, astragalus, and cat’s claw for immunity; guarana and Cordyceps for energy; chicory root for constipation; lemon balm oil, ashwagandha, eleuthero, Siberian ginseng, and holy basil for stress; sage and black cohosh for menstrual pain; coconut oil and curry powder for Alzheimer’s disease; saw palmetto for prostate health; sandalwood bark to prevent aging; garlic for high cholesterol; peppermint oil for allergies; artichoke extract and green papaya for digestion; echinacea for colds; chondroitin sulfate and glucosamine for joint pain; milk thistle for hepatitis; St. John’s wort for depression; and tongkat ali for sexual potency. Although the size and cost of clinical studies have increased dramatically since the days of James Lind, the claims made by alternative healers are testable—eminently testable.

  When pharmaceutical companies make drugs and biologicals, the rules are clear. Company scientists first test the product in animals. If the results are promising, they take the next step, testing it in progressively larger numbers of people. If the results are still promising, they perform a definitive (so-called Phase III) study proving that the product is safe and that it works. For example, two rotavirus vaccines are distributed in the United States (I’m the co-inventor of one of them). These vaccines prevent a common cause of diarrhea and dehydration in infants. Before the existence of a rotavirus vaccine, about 70,000 children in the United States were hospitalized with dehydration caused by rotavirus every year; in the developing world, rotavirus killed 2,000 children every day.

  Making a rotavirus vaccine wasn’t easy. The Phase III trial for one rotavirus vaccine, RotaTeq, included more than 70,000 children from eleven countries, tested for four years at a cost of about $350 million. If stacked one on top of another, patients’ records from that trial would have exceeded the height of the Sears Tower in Chicago. The FDA and EMEA allowed the manufacturer of RotaTeq to make claims about safety and effectiveness only after those claims had been supported by rigorous scientific studies; otherwise, it wouldn’t have licensed the product.

  The situation for plants, herbs, and dietary supplements is different. Because of the Supplement Act, the FDA doesn’t regulate them, so they don’t have to be tested before they’re sold. Sometimes supplements are tested by the National Center for Complementary and Alternative Medicine (NCCAM), a branch of the National Institutes of Health. One difference between the FDA
and NCCAM is that the FDA requires products to be tested before they’re sold, whereas NCCAM might test some products after they’ve been put on the market. If researchers funded by NCCAM find that dietary supplements don’t work or have harmful side effects, they publish their results in scientific journals. No product recall. No change in the label. No FDA warnings. If people don’t read scientific journals, they won’t know that claims on the label are false and misleading.

  The driving force behind the creation of NCCAM was Tom Harkin, a popular senator from Iowa who believed his allergies had been cured by eating bee pollen. Harkin figured that the only reason alternative remedies hadn’t been brought into the mainstream was that they hadn’t been properly tested. Once they were tested and everyone could see that they really worked, alternative medicine would be embraced by modern science and paid for by insurance companies. Since its birth, in 1999, NCCAM officials have spent about $1.6 billion studying alternative therapies. They’ve spent $374,000 of taxpayer money to find out that inhaling lemon and lavender scents doesn’t promote wound healing; $390,000 to find out that ancient Indian remedies don’t control Type 2 diabetes; $446,000 to find that magnetic mattresses don’t treat arthritis; $283,000 to discover that magnets don’t treat migraine headaches; $406,000 to determine that coffee enemas don’t cure pancreatic cancer; and $1.8 million to find out that prayer doesn’t cure AIDS or brain tumors or improve healing after breast reconstruction surgery. Fortunately, NCCAM has recently abandoned these kinds of studies, choosing instead to focus on studies of dietary supplements and pain relief.

  Let’s assume for a moment that everyone wants what’s best for the patient. Alternative healers believe that ancient medicine is of value. And mainstream doctors and pharmaceutical companies believe that modern science has the most to offer. Peter Medawar, a Nobel Prize–winning immunologist, calls the battle for recognition by those who promote various remedies a “kindly conspiracy.” “Exaggerated claims for the efficacy of a [therapy] are very seldom the consequence of any intention to deceive,” he writes. “They are usually the outcome of a kindly conspiracy in which everybody has the best intentions. The patient wants to get well, his physician wants to have made him better, and the pharmaceutical company would like to put it into the physician’s power to have made him so. The controlled clinical trial is an attempt to avoid being taken in by this conspiracy of goodwill.”

  Using Medawar’s logic, terms like conventional and alternative medicine are misleading. If a clinical trial shows that a therapy works, it’s not an alternative. And if it doesn’t work, it’s also not an alternative. In a sense, there’s no such thing as alternative medicine. For example, Hippocrates used the leaves of the willow plant to treat headaches and muscle pains. By the early 1800s, scientists had isolated the active ingredient: aspirin. In the 1600s, a Spanish physician found that the bark of the cinchona tree treated malaria. Later, cinchona bark was shown to contain quinine, a medicine now proven to kill the parasite that causes malaria. In the late 1700s, William Withering used the foxglove plant to treat people with heart failure. Later, foxglove was found to contain digitalis, a drug that increases heart contractility. More recently, artemisia, an herb used by Chinese healers for more than a thousand years, was found to contain another anti-malaria drug, which was later called artemisinin. “Herbal remedies are not really alternative,” writes Steven Novella, a Yale neurologist. “They have been part of scientific medicine for decades, if not centuries. Herbs are drugs and they can be studied as drugs. My problem is with the regulation and marketing of specific herbal products, because they often make claims that are not backed by evidence.” Unfortunately, when natural products promoted by alternative healers have been put to the test, they’ve often fallen far short of their claims.

  Although mainstream medicine hasn’t found a way to treat dementia or enhance memory, practitioners of alternative medicine claim that they have: ginkgo biloba. As a consequence, ginkgo is one of the ten most commonly used natural products, netting hundreds of millions of dollars a year for its manufacturers. Unfortunately, sales exceed claims. Between 2000 and 2008, the National Institutes of Health funded a collaborative study by the University of Washington, the University of Pittsburgh, Wake Forest University, Johns Hopkins University, and the University of California at Davis to determine whether ginkgo worked. More than 3,000 elderly adults were randomly assigned to receive ginkgo or a placebo (a sugar pill). Decline in memory and onset of dementia were the same in both groups. In 2012, a study of more than 2,800 adults found that ginkgo didn’t ward off Alzheimer’s disease.

  Another example is St. John’s wort. Every year, ten million people suffer major depression in the United States, and every year 35,000 people kill themselves. For each successful suicide, eleven more have tried. Depression is a serious illness; to treat it, scientists have developed medicines that alter brain chemicals such as serotonin. Called selective serotonin reuptake inhibitors (SSRIs), these drugs are licensed by the FDA. Because they’ve been shown to help with severe depression, doctors recommend them. Practitioners of alternative medicine, however, have a better idea—a more natural, safer way to treat depression: St. John’s wort. Because so many people use St. John’s wort, and because depression, if not properly treated, can lead to suicide, NCCAM studied it. Between November 1998 and January 2000, eleven academic medical centers randomly assigned 200 outpatients to receive St. John’s wort or a placebo, finding no difference in any measure of depression.

  Another favorite home remedy is garlic to lower cholesterol. Because high cholesterol is associated with heart disease, because heart disease is a leading cause of death, because lipid-lowering agents lower cholesterol, and because many people are choosing garlic instead of lipid-lowering agents, researchers studied it. In 2007, Christopher Gardner and coworkers at Stanford University School of Medicine evaluated the effects of garlic on 192 adults with high levels of low-density lipoprotein cholesterol (bad cholesterol). Six days a week for six months, participants received either raw garlic, powdered garlic, aged garlic extract, or a placebo. After checking cholesterol levels monthly, investigators concluded, “None of the forms of garlic used in this study … had statistically or clinically significant effects on low-density lipoprotein cholesterol or other plasma lipid concentrations in adults with moderate hypercholesterolemia.” In other words, patients who choose garlic to treat their bad cholesterol are choosing to do nothing for a problem that could lead to severe and even fatal heart disease.

  Saw palmetto is also popular. As a man ages, his prostate enlarges, which blocks the flow of urine. If untreated, prostate enlargement can cause urinary tract infections, bladder stones, and kidney failure. Fortunately, medicines that relax muscles within the prostate or reduce its size have been available for years. But practitioners of alternative medicine prefer saw palmetto; more than 2 million men use it.

  In 2006, NCCAM supported a study at the University of California at San Francisco, the San Francisco Veterans Affairs Medical Center, and Northern California Kaiser Permanente. Investigators assigned 225 men with moderate to severe symptoms of prostate enlargement to receive either saw palmetto or a placebo twice daily for a year, finding no difference between the two groups in urinary flow rate, prostate size, or quality of life.

  Five years later, the study was repeated, this time with higher doses. Researchers from Washington University School of Medicine, in St. Louis, studied 369 men who received increasing doses of saw palmetto or a placebo. Again, no change in urinary symptoms. “Now we know that even very high doses of saw palmetto make absolutely no difference,” said study author Gerald Andriole, chief of urologic surgery at the school. “Men should not spend their money on this herbal supplement as a way to reduce symptoms of an enlarged prostate because it clearly does not work any better than a sugar pill.”

  A choice to believe the hype about saw palmetto was a choice to risk the occasionally severe complications of prostate enlargement. Again, natural wasn�
�t better. It was worse.

  Another popular remedy is milk thistle. “A most interesting tonic herb from the tradition of European folk medicine is milk thistle, Silybum marianum,” wrote Andrew Weil in 1995. “The seeds from this plant yield an extract, silymarin, that enhances metabolism of liver cells and protects them from toxic injury. I recommend this herb to all patients with chronic hepatitis and abnormal liver function.” Unfortunately, Weil’s recommendation didn’t stand up to scientific study. In 2011, Dr. Michael Fried, of the University of North Carolina at Chapel Hill, led a group of investigators in determining whether milk thistle helped patients with chronic hepatitis C. More than 150 people infected with hepatitis C virus were given either milk thistle or a placebo. Then investigators determined the amount of liver damage, as well as the quantities of hepatitis C virus in blood. They found no difference between the two groups.

  Alternative healers also recommend chondroitin sulfate and glucosamine for joint pain. In 2006, Daniel Clegg, of the University of Utah, led a group of investigators to see whether it worked. They studied more than 1,500 people who were given either chondroitin sulfate alone, glucosamine alone, both, a placebo, or Celebrex (an FDA-licensed anti-inflammatory drug). Only Celebrex worked.

  Perhaps the most popular herbal remedy in the United States is echinacea. Used to treat colds, it’s a $130-million-a-year business. In 2003, James Taylor and coworkers at the University of Washington, in Seattle, studied more than 400 children with colds who had received either echinacea or a placebo for ten days. The only difference: children taking echinacea were more likely to develop a rash.

  Not all the news is grim. Some dietary supplements actually might be of value. Of the 51,000 new supplements on the market, four might be of benefit for otherwise healthy people: omega-3 fatty acids to prevent heart disease, calcium and vitamin D in postmenopausal women to prevent bone thinning, and folic acid during pregnancy to prevent birth defects.