Breast cancer patients who take the dietary supplements known as antioxidants, as well as iron, vitamin B12, and omega-3 fatty acids, during chemotherapy may be at increased risk of disease recurrence and death, according to new study results appearing in the Journal of Clinical Oncology.
Led by researchers at the SWOG Cancer Research Network, a cancer clinical trials network funded by the National Cancer Institute (NCI) through the National Institutes of Health, the study confirms previous medical guidance advising cautious use of any supplements, other than a multivitamin, for cancer patients undergoing chemotherapy.
A small but growing body of research in the last 20 years shows that, despite their cancer-fighting reputation, antioxidants such as vitamin E, beta-carotene, and selenium can actually increase risk of some cancers, cause some cancers to return after treatment, or interfere with the effects of chemotherapy. As part of the nation’s oldest and largest publicly-funded cancer research network, SWOG has conducted some of this work. Its landmark Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed that vitamin E supplementation increases the risk of prostate cancer in healthy men.
What’s unique about the new study, led by Christine B. Ambrosone, PhD, of Roswell Park Comprehensive Cancer Center, is that it is the first investigation of the effects of supplement use during breast cancer treatment, and only the second to investigate the effects of supplement use during any kind of cancer treatment. The first was conducted by Charles Fuchs, MD, MPH, the director of Yale Cancer Center, who found that vitamin C may be helpful for people undergoing chemotherapy treatment for colorectal cancer.
“Although this is an observational study and the number of users of supplements was fairly small, the results are compelling,” said Ambrosone, chair of the Department of Cancer Prevention and Control at Roswell Park. “Patients using any antioxidant before and during chemotherapy had an increased risk of their breast cancer returning and, to a lesser degree, had an increased risk of death. Vitamin B12, iron, and omega-3 fatty acid use was also associated with poorer outcomes.”
Ambrosone conducted her study as part of S0221, a randomized phase III SWOG trial determining the best dose and schedule for using three chemotherapy drugs – doxorubicin, cyclophosphamide, and paclitaxel – as adjuvant therapy for high-risk, early-stage breast cancer. In its first iteration, the trial enrolled 2,716 patients between 2003 and 2010. Patients were followed for a median of six years to identify any side effects from the chemotherapy combinations tested and to measure how long, if ever, it took for their breast cancer to return.
Whether vitamin and mineral supplements, in particular the type known as antioxidants, help or hurt cancer patients is a matter of debate and dueling research findings. Some evidence suggests that antioxidants can interfere with the cancer-killing effects of chemotherapy. That’s because these chemical treatments cause oxidative stress, a chemically-triggered reaction in the body, which in turn kills cancer cells. But antioxidants fight oxidative stress, which means they can blunt the effects of chemotherapy. At the same time, a few studies, such as Fuchs,’ show benefits to cancer patients who take dietary supplements.
To better understand the role supplements might play in chemotherapy response, Ambrosone and her team asked every woman and man randomized onto S0221 whether they would answer detailed questionnaires about their use of dietary supplements – first at the time they were assigned to a treatment group, then again six months after their chemotherapy was complete. Of the 2,014 patients eligible for this part of the study, 1,607 – or 80 percent – agreed.
In the end, 1,134 patients completed both surveys, and of these, 18 percent used at least one antioxidant daily, while 44 percent took multivitamins. Here’s what researchers found:
Patients who reported taking any antioxidant – vitamins A, C, E and carotenoids and Coenyzme Q10 – were 41 percent more likely to have their breast cancer return when they took the supplements both before and during chemotherapy treatment
Patients had a similar, but weaker, increased risk of death when taking those antioxidants
Patients taking vitamin B12, iron, and omega-3 fatty acid supplements were at significantly greater risk of breast cancer recurrence and death
Patients taking multivitamins showed no signs of poorer or better outcomes after chemotherapy
Ambrosone cautions that her study results are not definitive enough to influence how doctors treat cancer patients. To do that, she notes, the research community would need to run a larger, randomized trial testing groups who do and do not take supplements to get a clear and strong connection. However, she said the results do support the current cautious approach to supplement use for people undergoing chemotherapy.
“People diagnosed with any cancer should talk with their doctors about whether they should be taking vitamins or other supplements,” she said. “I’d recommend that they try to get their vitamins and minerals – including antioxidants – from food. With a healthy and balanced diet, you can get all the nutrients your body needs, even while undergoing chemo.”
If changes in taste or loss of appetite related to the effects of cancer treatment are making whole vegetables, fruits, and grains unappealing or difficult to eat, Ambrosone advises, patients should seek out guidance from their medical team or a dietician to find out ways to incorporate these foods into their diets.
Cancer dietitian Lisa Cianciotta often finds herself sitting across from a patient who suddenly fishes a bottle of antioxidant supplements from their bag and says, “My friend told me this works really well,” or “I read on the internet that this is supposed to be really good for cancer.”
Although taking an antioxidant pill sounds harmless, Cianciotta, a clinical dietitian who works with cancer patients at NewYork-Presbyterian Hospital in New York City, knows well that this popular dietary supplement can interfere with a patient’s radiation or chemotherapy.
But many patients with cancer believe these over-the-counter vitamins, minerals, or herbal remedies will help them, and most use at least one dietary supplement alongside their cancer treatment.
And that leaves Cianciotta with a delicate conversation ahead of her.
Cancer Diagnosis & Treatment Insights
Learn from two physicians about what advice they have for patients during their cancer journey.
Drug-supplement interactions are complex, often varying by supplement, cancer, and treatment type, and can do more harm than good. Popular dietary supplements may, for instance, cancel the effects of a cancer treatment, making it less effective, or increase serious side effects, such as liver toxicity. But in other cases, supplementation, such as vitamin D for patients who lack the vitamin, may be beneficial, Cianciotta says.
These drug-supplement interactions can be hard to pinpoint, given that more than two-thirds of doctors don’t know their patients are using supplements.
Here’s what patients need to know about the potential risks of supplement use during treatment, and how oncologists can address this thorny, often poorly understood topic with patients.
The Complex Drug-Supplement Landscape
The list of dietary supplements and how they can interact with different treatments and cancer types is long and nuanced.
But certain supplements appear to affect cancer treatments regardless of other things and should be avoided. Any supplement that strongly alters the body’s levels of the protein cytochromes P450 is one example. This group of enzymes plays a key role in metabolizing drugs, including chemotherapy and immunotherapy agents.
Certain supplements – most notably St. John’s wort extract – may decrease or increase the activity of cytochrome P450, which can then affect the concentrations of anticancer drugs in the blood, says William Figg, PharmD, an associate director of the Center for Cancer Research at the National Cancer Institute in Bethesda, MD. Studies show, for instance, that this common herbal supplement can increase the activity of cytochrome P450, resulting in lower levels of cancer drugs.
Outside of drug metabolism, patients with hormone-related cancers, such as breast and prostate cancers, should steer clear of dietary supplements that can alter levels of testosterone or estrogen, Figg says. The evergreen shrub ashwagandha, for example, is marketed to reduce stress and fatigue, but can also increase testosterone levels – a potential problem for those with prostate cancer receiving androgen deprivation therapy, which lowers testosterone levels.
Many oncologists counsel patients against using antioxidant-based dietary supplements – particularly turmeric and green tea extract – while they have radiation therapy and certain chemotherapies. These therapies work by creating an abundance of highly reactive molecules called free radicals in tumor cells, which increase stress within these cells, ultimately killing them off. Antioxidants, in theory, can neutralize this effect, says Skyler Johnson, MD, a radiation oncologist at the Huntsman Cancer Institute at the University of Utah, Salt Lake City. Some studies suggest that antioxidant supplements may lessen the effects of radiation and chemotherapy, although the evidence is mixed.
Some dietary supplements, including high-dose green tea extract and vitamin A, can cause kidney or liver toxicity, and “many cancer patients already have compromised kidney or liver function,” says Jun J. Mao, MD, chief of integrative medicine at Memorial Sloan Kettering Cancer Center in New York City. Even herbs that don’t interfere with how well a cancer drug works, such as stevia, can increase treatment-related side effects, such as nausea and vomiting.
Another potential problem with dietary supplements: It’s nearly impossible to know exactly what’s in them. For instance, just last year, the FDA sent nearly 50 warning letters to companies marketing dietary supplements. The issue is that federal regulations governing production are less strict for supplements than for medications. As a result, some supplements contain ingredients not listed on the label.
One historical example was the supplement PC-SPES, a mix of eight herbs, marketed to men with prostate cancer. The supplement was recalled in 2002 after certain batches were found to contain traces of prescription drugs, including diethylstilbestrol, ethinyl estradiol, warfarin, and alprazolam.
To further complicate matters, some dietary supplements can be helpful. Most patients with cancer “are malnourished and missing out on nutrients they could be getting from food,” says Cianciotta.
Patients are tested routinely for vitamin deficiencies and receive supplements as needed, she says. Vitamin D and folic acid are two of the most common deficiencies in this patient population. Vitamin D supplementation can improve outcomes in patients who have received a stem cell transplant by aiding engraftment and rebuilding the immune system, while folic acid supplementation can help to raise low red blood cell counts and hemoglobin levels. Slideshow
Although she rarely sees vitamin toxicity, Cianciotta stresses that more is not always better and supplement use, even when it seems safe or warranted due to a deficiency, should be taken under supervision, and monitored carefully by the patient’s care team.
Bringing Supplement Use Into the Light
Too often, providers are unaware of a patient’s supplement use.
A core reason: Dietary supplements are often touted as natural, which many patients equate with safety, says Samantha Heller, a senior clinical nutritionist at New York University Langone Health in New York City.
That means patients may not know a supplement can act like a drug and interfere with their cancer treatment, and thus may not see the importance of telling their doctor.
Still, the promise of herbs, vitamins, and minerals can be alluring, and there are many reasons patients decide to partake. One major appeal: Dietary supplements can help some patients feel empowered.
“Cancer is a disease that takes away a lot of control from the individual. Taking supplements or herbs is a way to regain some sense of control,” says Mao.
The phenomenon can also be cultural, he says. Some people grow up taking herbs and supplements to stay healthy or combat health woes.
Pressure or advice from family or friends who may think they are helping a loved one with their dietary recommendations may play a role as well. Friends and family “cannot prescribe chemo, but they can buy herbs and supplements,” Mao says.
Patients seeking greater control over their health or who feel high levels of anxiety may be more likely to take suggestions from friends and family or more likely to believe false or misleading claims about the efficacy or safety of supplements, explains medical oncologist William Dahut, MD, chief scientific officer for the American Cancer Society.
Plus, social media often amplifies and normalizes this misinformation, notes Johnson. In a 2021 study published in the Journal of the National Cancer Institute, he and colleagues found that one-third of the most popular articles on cancer treatment posted to social media in 2018 and 2019 contained false, inaccurate, or misleading information that was often harmful.
Some of the false claims centered on unproven, potentially unsafe herbal remedies, according to Johnson. These included “lung cancer can be cured with cannabis oil” and “golden-berries cure and prevent cancer.”
Given exaggerated claims of “cures,” some patients may keep their supplement use under the radar out of fear they will be judged or criticized.
“Clinicians should avoid making patients feel judged or telling people not to go online to do their own research,” Johnson says.
Guiding patients, instead, to accurate sources of online information may be one way to help patients feel empowered, he says. Cancer.gov and the Memorial Sloan Kettering Cancer Center’s About Herbs database provide accessible and accurate information on dietary supplements and cancer treatment for both health care professionals and patients, he notes.
If a particular supplement is not safe during treatment, providers should be able to explain why, says Cianciotta. In a recent study, 80% of health care providers surveyed believed that interactions between herbals and medications could be problematic, but only 15% could explain why.
“Being able to explain why we are discouraging a particular supplement right now tends to be much better received than just telling a patient not to take something, because it is bad,” she says.
Another key is listening closely to patients to understand why they may be taking a particular supplement. Does the patient feel out of control? Is nausea a problem? Slideshow
“Allowing patients to tell you why they are using a particular supplement will often reveal unmet needs or psychosocial challenges,” Mao says. This information can allow providers to suggest an evidence-based alternative, such as mindfulness meditation or acupuncture to manage stress.
And if a patient has received a dietary supplement from well-meaning family and friends?
“Simply telling a patient that a given supplement is useless or harmful could create family tension,” says Mao.
Instead, he recommends reframing the issue.
“We want to have a better understanding of how patients are tolerating chemo or immunotherapy before throwing other things on top of it. Let them know that now may just not be the right time to add a supplement to the mix,” Mao says.
The bottom line: “Patients want to play an active role in their own care, and we want to help them do that in a safe way,” he says.
Supplements are commonly used by individuals with indications for lipid-lowering therapy, but evidence of their effectiveness to lower low-density lipoprotein cholesterol (LDL-C) is lacking, particularly when compared with statins.
Objectives
The trial objective was to compare the efficacy of a low-dose statin with placebo and 6 common supplements in impacting lipid and inflammatory biomarkers.
Methods
This was a single-center, prospective, randomized, single-blind clinical trial among adults with no history of atherosclerotic cardiovascular disease (ASCVD), an LDL-C of 70 to 189 mg/dL, and an increased 10-year risk of ASCVD. Participants were randomized to rosuvastatin 5 mg daily, placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, or red yeast rice. The primary endpoint was the percent change in LDL-C from baseline for rosuvastatin 5 mg daily compared with placebo and each supplement after 28 days. The primary endpoint was evaluated in a hierarchical fashion with rosuvastatin first compared with placebo, then each supplement in a prespecified order using analysis of covariance.
Results
A total of 190 participants completed the study. The percent LDL-C reduction with rosuvastatin was greater than all supplements and placebo (P < 0.001). The difference in LDL-C reduction with rosuvastatin compared with placebo was −35.2% (95% CI: −41.3% to −29.1%; P < 0.001). None of the dietary supplements demonstrated a significant decrease in LDL-C compared with placebo. Adverse event rates were similar across study groups.
Conclusions
Among individuals with increased 10-year risk for ASCVD, rosuvastatin 5 mg daily lowered LDL-C significantly more than placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice.
Discussion
In this randomized, placebo-controlled, parallel-arm trial, the lowest available dose of rosuvastatin, 5 mg daily, classified as a moderate-intensity statin, produced significantly greater LDL-C reduction compared with placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice in patients with increased 10-year ASCVD risk and an LDL-C >70 mg/dL. None of the dietary supplements demonstrated a significant decrease in LDL-C compared with placebo. However, the garlic supplement increased LDL-C compared with placebo. Compared with placebo and supplements, the low-dose statin regimen improved other lipid biomarkers including total cholesterol and serum triglycerides. Adverse events were minimal in all groups. A notable finding in the current trial is that garlic supplementation increases LDL-C. In 2007, a randomized clinical trial of 3 separate garlic preparations compared with placebo in participants with hypercholesterolemia demonstrated a trend toward LDL-C increase in all 3 garlic preparations, though the increase was not statistically significant.9 A 2021 meta-analysis of the impact of garlic extract also demonstrated no significant change in LDL-C among individuals with coronary artery disease.10
The use of dietary supplements by the U.S. population has increased exponentially during the last 3 decades. When DSHEA was passed in 1994, about 600 U.S. manufacturers were producing an estimated 4,000 products. Two decades later, more than 90,000 products were available on the U.S. market.1 In the NHANES (National Health and Nutrition Examination Survey) conducted in 37,958 adults from 1999 to 2012, 52% of respondents reported that they were taking daily dietary supplements.11 By 2019, 77% of adults were taking dietary supplements, and 18% of those surveyed reported that they were using supplements to promote heart health.12 Patient preference for nonstatin alternatives is multifactorial and driven in part by beliefs regarding statin-associated hepatotoxicity, muscle symptoms, and neurological side effects.13,14 Limited government regulation of supplements and their claims for benefits, along with an abundance of statin misinformation, create an environment that deters the U.S. population from taking well-regulated, inexpensive, safe, and potentially life-saving medications with decades of supporting evidence.15 Although the use of dietary supplements to promote cholesterol health is widespread, limited data are available to demonstrate their efficacy or safety, particularly when compared with statin therapy.
A meta-analysis of clinical trials and prospective cohort studies including over 2 million individuals demonstrated that multivitamin/mineral supplementation is not associated with a difference in cardiovascular mortality (relative risk: 1.0; 95% CI: 0.97-1.04) in the general population.16 Although data exist demonstrating significant LDL-C reductions with red yeast rice supplementation, different product formulations and manufacturers can result in varying levels of efficacy, or lack thereof, as seen in the current trial.17 Plant sterols are endorsed as an option to lower blood cholesterol levels in the 2019 European Society of Cardiology/European Atherosclerosis Society guidelines for the management of dyslipidemias; however, there is controversy regarding their efficacy and some suggestion that they may be atherogenic.18,19 Similar to SPORT, a 2017 meta-analysis including 13 randomized clinical trials of cinnamon supplementation failed to show a significant decrease in LDL-C.20 A 2017 meta-analysis of turmeric and the lowering of blood lipid levels suggested a possible decrease in LDL-C and serum triglycerides with its use in patients with type 2 diabetes mellitus or metabolic syndrome, but stands in contrast to a 2015 meta-analysis of curcumin that did not demonstrate significant changes in lipid parameters in a more heterogeneous population.21,22 A lack of transparency and consistency regarding supplement composition clearly can impact the observed pharmacological effect. The U.S. Preventive Services Task Force recently released a statement about certain supplements and cardiovascular health, concluding that there was insufficient evidence to support their use.23
DSHEA provided a definition of the term dietary supplement for the FDA. A dietary supplement is any product taken by mouth that contains a “dietary ingredient” intended to supplement the diet. DSHEA categorizes these products as foods, not drugs, and requires that each be labeled as a dietary supplement. DSHEA also defined the term dietary ingredient as a vitamin, mineral, herb or other botanical, amino acid, enzymes or tissues from organs or glands, or a concentrate, metabolite, constituent, or extract.24 These categories are very broad and allow marketing of a wide variety of products. Although categorized as foods, not drugs, some dietary supplements interact with the cytochrome system and can affect the metabolism of prescription drugs.25 Prior data also demonstrate that dietary supplements may produce harm. An estimated 23,000 emergency department visits in the United States every year are attributed to adverse events related to dietary supplements.26 There are many described cases of supplements with microbial contamination, heavy metal contamination, and addition of unapproved prescription ingredients.27,28 DSHEA specifies that supplements must be manufactured free of contamination or adulteration but allows them to be sold in the United States without providing proof of their quality to the FDA; the burden rests with the FDA to prove a supplement is unsafe, which presents a formidable challenge to enforcement.1
The current trial provides evidence that certain supplements marketed or promoted for “cholesterol health” do not significantly lower LDL-C compared with placebo, and are inferior to a moderate-intensity statin. These data also demonstrate the expected improvement in other lipid biomarkers with low-dose rosuvastatin, but no difference for supplements compared with placebo. LDL-C is a well-established risk factor for the development of ASCVD. Similar to the approach studied in SPORT, the 2018 American Heart Association/American College of Cardiology/Multisociety Blood Cholesterol guidelines suggest a discussion regarding the use of moderate-intensity statin therapy for patients with a 10-year risk of ASCVD between 5% and 20%.8 Rosuvastatin 5 mg is a moderate-intensity statin, and the percent decrease in LDL-C observed in the current study aligns with prior findings.29
Study limitations
Although the trial duration was sufficient to see significant LDL-C, total cholesterol, and serum triglyceride lowering in participants randomized to a low-dose statin, the relatively short study period may not fully capture the effect on lipid biomarkers of supplements with a longer duration of use. A 28-day trial duration was chosen based on the 2018 blood cholesterol guidelines recommendation to “assess adherence and percentage response to LDL-C lowering medications and lifestyle changes with repeat measurement in 4 to 12 weeks.”8 Although the findings have narrow confidence intervals, the small sample size cannot rule out a small benefit from 1 or more of the supplements. Similarly, although the trial measured biomarkers known to predict and impact future cardiovascular risk, the effect of supplements on cardiovascular outcomes cannot be determined by a trial of this size and scope. The lack of effect of rosuvastatin on hsCRP is inconsistent with prior data, likely due to the small sample size and low dose used in SPORT.30 The small sample size also does not allow for meaningful subgroup analysis. Eighty-nine percent of participants were non-Hispanic White race, possibly limiting the applicability of study results to other races.
Conclusions
In this single-center, prospective, randomized, single-blind clinical trial of patients with elevated LDL-C and increased 10-year ASCVD risk, a low-dose statin taken daily lowered LDL-C significantly more than placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice. No supplements significantly lowered LDL-C compared with placebo. No supplement demonstrated a change in other lipid or inflammatory biomarkers suggestive of potential cardiovascular benefit compared with placebo. These findings do not support the cholesterol health claims made by supplement manufacturers. Patients should be educated about the lack of benefit of these supplements on important cardiovascular risk factors.
Pieter Cohen’s brush with death came at a most inconvenient time: just as he was about to nail another menacing ingredient in a dietary supplement.
Hiking last August in New Hampshire with his wife and three children, Cohen, an internist at Cambridge Health Alliance in Massachusetts, stumbled and fell. A rock punctured his left calf. “It was a little cut, but deep,” recalls his wife, Lauren Budding. By the next day, bacteria were coursing through Cohen’s bloodstream. The leg turned red and swelled. His blood pressure dropped precipitously. Cohen was rushed to a community hospital and soon after by ambulance to a trauma unit in Boston.
Doctors worked feverishly to stabilize him and stop the spread of infection. Over the next few days, the threat of death ebbed, though the risk that he would never walk normally remained. Cohen, meanwhile, fretted about the same matters he usually did: consumers, including his patients, who might be swallowing dietary supplements spiked with drugs. Bedbound and in searing pain, he asked for his computer. His wife refused.
“I’m like, ‘I’m sorry, this person needs to sleep,’” she told the hospital staff. So Cohen had his mother smuggle in the laptop, along with data sets concealed inside The Boston Globe. “I could work on the manuscript when Lauren wasn’t looking,” he reasoned.
Eleven days after the accident, and after the fourth of what would be five surgeries, Cohen and two collaborators submitted their paper to Drug Testing and Analysis. The report was unnerving: At least a dozen supplements sold in the United States for weight loss, enhanced brain function, and improved athletic performance contained a synthetic stimulant. The compound, which Cohen and his co-authors named DMBA, resembled methamphetamine in its chemical structure. It had never been tested in people, only in two animal studies from the 1940s. “Its efficacy and safety are entirely unknown,” they wrote.
By now ensconced in a hospital bed in his living room and waiting for skin grafts to heal, Cohen appealed to the journal: “I can’t walk, I’m totally available. Can you guys crank this review?” The paper was published online a month later, last October. In April of this year, the U.S. Food and Drug Administration (FDA) issued warning letters to 14 companies selling products containing DMBA. “The FDA considers these dietary supplements to be adulterated,” it wrote. And boom, Cohen was on to his next project.
FDA
Since 2005, when he found his patients were being sickened by a Brazilian weight loss supplement containing anti-depressants and thyroid hormones, Cohen has become something of a mix of Indiana Jones and Sherlock Holmes in the supplement world. With chemist colleagues in the United States, Brazil, and Europe, he hunts for drugs illegally buried in supplements. Then he goes public. His unorthodox public relations strategy is to publish research fast in low-profile, specialty journals, reach out to a network of hand-picked journalists, and, he hopes, ultimately inspire new regulations. He has virtually no funding, nor does he aspire to secure any. “I have total freedom,” he says. So far, he and his collaborators have identified three hidden stimulant drugs in supplements.
Cohen’s discoveries highlight a broader problem, he and others contend: a dys-functional system for policing dietary supplements. “It comes to this,” says Paul Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, who published a book called Do You Believe in Magic? about alternative medicine. “Essentially a private citizen [is] doing the testing to make sure what’s on the label is in the bottle. … It’s absurd.”
But that private citizen is having an impact. FDA actions have cited Cohen’s work or followed his publications, as the DMBA warnings did. He has also caught the attention of supplement companies, including in a lawsuit filed against him in April seeking $200 million in damages. “Everything I write gets such scrutiny” that it creates tremendous pressure, he says. “I want our science to be bulletproof.”
THE MODERN SUPPLEMENT ERA began in 1994, when Congress passed the Dietary Supplement and Health Education Act, or DSHEA (pronounced duh-shay-uh). In the decades before, the supplements industry was overwhelmingly focused on vitamins and minerals. Much of the regulation centered on recommended daily allowances of products like vitamin C, iron, or calcium.
DSHEA established the first broad framework for regulating supplements. It also gave supplements a legal definition: as substances intended to “supplement the diet,” containing “dietary ingredients” such as herbs, botanicals, or vitamins.
At the same time, the law sharply curtailed FDA’s power. Companies were not required to notify FDA provided the dietary ingredient had a history of use before the law was passed. For the first time, DSHEA allowed them to make claims on the label suggesting supplements affected the structure or function of the body—for example, by boosting the immune system or protecting prostate health. And DSHEA codified a loose arrangement: Under the law, as FDA notes on its website, “unlike drug products that must be proven safe and effective for their intended use before marketing, there are no provisions in the law for FDA to ‘approve’ dietary supplements … before they reach the consumer.” The agency can act only after a supplement is on the market and evidence shows it’s unsafe.
Whereas the industry and many consumers celebrated DSHEA for expanding access to supplements, the act was skewered by physicians, journalists, and consumer protection groups. In an editorial shortly before DSHEA passed, The New York Times called it the “snake oil protection act,” suggesting that it was “about the right of unscrupulous companies and individuals to maximize profits by making fraudulent claims.” Meanwhile, the industry grew exponentially: Since 1994, the number of dietary supplements marketed in the United States has swelled from about 4000 to more than 75,000. About $36 billion worth were sold last year.
The ink had barely dried on DSHEA when trouble began. Within 2 years, a Chinese herb called ma huang or ephedra, which companies promoted as a legal alternative to ecstasy, was under scrutiny. Although a natural product, the herb contains the chemical ephedrine, which stimulates the nervous system and constricts blood vessels. By early 1996, it had been linked to at least 15 deaths. Meanwhile, FDA was regularly issuing warnings about liver, kidney, and other health risks tied to supplements.
“There are authentic dietary supplements—multivitamins, calcium, iron—which do supplement the diet” and can help many people, says rheumatologist and immuno-logist Donald Marcus of Baylor College of Medicine in Houston, Texas, an early critic of the supplement industry. But other supplements, like “St. John’s wort, echinacea … are used as medicine,” he points out. In part because “botanicals are complex mixtures of chemicals,” supplements in this category present “a serious and growing public health problem,” Marcus and a colleague, pharmacologist Arthur Grollman of the State University of New York at Stony Brook, wrote in TheNew England Journal of Medicine in 2002. Just how big a problem was unclear, however, because FDA hears about only a tiny fraction of adverse events from the companies, they noted.
Meanwhile, concerns about ephedra continued to mount. Army commissaries stopped selling it after it was implicated in the deaths of soldiers; after a 16-year-old taking the supplement died in Illinois, that state halted ephedra sales, too. FDA banned ephedra in 2004, after a 23-year-old Major League Baseball pitcher collapsed and died during practice and was found to be taking the herb.
CDC; Journal of the Academy of Nutrition and Dietetics; CDC; NIH
Cohen’s initiation into supplements came on the job. After finishing at the Yale School of Medicine, he began his residency and then went to work at Cambridge Health Alliance, a network of neighborhood clinics and community hospitals. Many of Cohen’s patients were Brazilian immigrants who had settled nearby.
Before long, the clinic’s patients developed mysterious symptoms. One woman came in “with palpitations, sweating, anxiety, but also feeling very tired,” remembers Daniel McCormick, a primary care internist in the same practice, who mentored Cohen in residency and shares a small office with him. Another wound up in the emergency room with kidney failure. One man lost his job after his urine tested positive for amphetamines.
Cohen made the connection: The patients were all taking weight loss pills known as rainbow diet pills, imported in bulk from Brazil. He sent the capsules off to a private lab for testing. The results shocked the doctors. The tests revealed amphetamines, thyroid hormones, diuretics, benzodiazepines, and antidepressants such as fluoxetine. “It was a pharmacopeia in one pill,” McCormick says. “It became clear to a lot of us that you could explain the symptoms from the diet pills.”
McCormick, Cohen, and three other colleagues conducted a survey of 307 Brazilian patients in their clinic and two nearby churches. They found that 18% in the clinic and 9% in the churches reported taking the pills, and two-thirds reported side effects. The paper was published online in 2007 in the obscure Journal of Immigrant and Minority Health.
“Less than 10 people are going to read that,” Cohen admitted to himself, because the journal is so specialized. “I knew that if I wanted more … I needed to do some outreach.” He contacted a local NPR reporter who had recently run a story on Latino bodegas selling antibiotics without a prescription, thinking he might be interested. The reporter invited him in for a studio interview. Folha de S.Paulo, a major Brazilian newspaper, contacted Cohen and ran a front-page story. Several years later, rainbow diet pills were banned in Brazil, though Cohen doesn’t know whether his work had anything to do with that.
Cohen thought the spiked supplements were an anomaly confined to the Brazilian neighborhoods. But then he got a call from an official in the drug division at FDA. “What you found in those diet pills shipped up from Brazil,” the official told him, “actually are found in weight loss supplements in the United States, and it’s a major problem.”
“WE HAVE BEEN WORRIED about contaminated dietary supplements for ages,” says Amy Eichner of the U.S. Anti-Doping Agency in Colorado Springs, Colorado. In 2003 and 2008, two elite swimmers lost the chance to compete in the Olympics after testing positive for performance-enhancing drugs they said they didn’t know were in their supplements. A similar fate befell two top cyclists. “That’s our nightmare scenario,” Eichner says.
Another with longstanding concerns is Patricia Deuster at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, who estimates that between 15% and 20% of military members are swallowing the supplements she and others fret about most: products marketed for bodybuilding, weight loss, and athletic performance. Another worrying category includes sexual enhancement products.
So in 2013, she and Eichner began systematically parsing supplement ingredients. Preliminary results, still unpublished, show that of the 169 high-risk products tested so far, 107 “contained at least one substance prohibited in sports,” Eichner says, and often that substance wasn’t listed clearly on the label. In many cases, she says, the ingredients are “either Schedule III substances on the Controlled Substances Act—that’s pretty major—or they have been specifically declared illegal by the FDA.”
At around that time, Cohen had an electrifying phone conversation. A lab scientist who tests supplements for companies confided in Cohen that he was deeply disturbed by the prevalence of an ephedra substitute, a stimulant called dimethylamylamine or DMAA, which kept appearing in products despite mounting concerns about its safety. That conversation was “the catalyst that opened this whole new world to me,” Cohen says.
With rainbow diet pills, he’d been focused on prescription drugs. Although DMAA had appeared in nasal sprays many decades ago before being removed from the market, it was now more like a “research chemical,” Cohen says, which some companies argued came from plants but which Cohen and many others disputed. He began searching for dangerous additives in supplements. FDA declared supplements containing DMAA illegal soon after, in 2013, but as Cohen quickly learned, there was no shortage of other targets.
“It’s a Sherlock Holmes situation,” he says with relish. “There’s a crime scene, there’s hints of struggle, people are dying after taking supplements. … What is actually going on?”
He found a perfect partner more than 5000 kilometers away near Utrecht, the Netherlands: Bastiaan Venhuis, a medicinal chemist who was also analyzing supplement ingredients. One of their first joint publications, in collaboration with NSF International, which tests food, supplements, and other consumer products, appeared online in the fall of 2013 in Drug Testing and Analysis. It examined a popular workout supplement called Craze. When Venhuis diluted the powder and ran it through his analyzer, telltale peaks indicated DEPEA, a methamphetamine analog.
To garner publicity, Cohen expanded the strategy he had followed with the Brazilian supplements. He sought a final manuscript from the journal about a week in advance and sent personal emails to upward of three dozen journalists, carefully selected for their prior coverage or relationships he had nurtured with them.
Cohen’s office buddy McCormick acknowledges that such media outreach, which he’s done himself, can feel awkward. It’s often regarded “as self-promotional,” McCormick says. “In the beginning I felt that way intensely and it was very uncomfortable. But … the vast number of hours that go into thinking about a research project, writing it, is just wasted” if it stops there, especially when it might have an impact on health policy.
Cohen has caught the attention not only of myriad journalists but of the supplement industry, too. In late April, a company called Hi-Tech Pharmaceuticals filed a $200 million claim for damages against Cohen and two colleagues, after the researchers published a paper suggesting Hi-Tech and other companies were marketing supplements that contained an amphetaminelike stimulant, BMPEA, which they mislabeled as Acacia rigidula, a shrub that grows in Texas and south into Mexico.
The company vigorously disputes that BMPEA is not part of the plant. “A real scientist concerned with objectivity would have taken steps to ensure that they weren’t disparaging products before they did this to the public,” says Edmund Novotny, an attorney in Atlanta who represents Hi-Tech.
Cohen wasn’t alone in singling out BMPEA: His study came about 18 months after FDA scientists reported detecting BMPEA in supplements, too, noting that nowhere could they find evidence that BMPEA was a natural component of plants. Soon after Cohen’s publication, FDA sent warning letters to five companies selling BMPEA-laced supplements, including Hi-Tech.
Like others, Cohen agrees that FDA’s supplement policing powers are too limited. But that doesn’t mean the agency has no muscle. “There’s so many things FDA could be doing that they’re not doing,” he says—for example, removing supplements from store shelves when companies don’t fully pass FDA inspections. The agency, Cohen believes, is overwhelmed by the sheer volume of supplements and discouraged by political forces from acting aggressively. When it comes to pulling a supplement ingredient, FDA’s attitude is “show us the dead bodies,” he says.
Mark Savage/Corbis
Top swimmer Jessica Hardy tested positive for a banned substance she said she didn’t know was in a supplement she was taking, “That’s our nightmare scenario,” says a U.S. antidoping official.
FDA officials wouldn’t put it that way, but they don’t entirely disagree. “Under current law, the FDA faces a high burden before it can take enforcement action on a dietary supplement,” wrote spokeswoman Lyndsay Meyer in an email message. The agency has its own frustrations. “The supply chain … is extremely fragmented,” Meyer wrote. “The individuals and businesses selling these products may operate out of residential homes, and distribute via internet, small stores, and mail … We recognize that more can and should be done.”
Nearly a year after his harrowing ordeal while hiking, Cohen has regained full function of his leg, though he still wears a black compression stocking. Sitting in his office in June, surrounded by photos of his three children and a jumble of supplement bottles patients have handed over to him for testing, Cohen shows little of the fatalism of others who have battled supplements for years. The reform movement “definitely has momentum,” he says. “I think we’re going to look back 50 years from now, and say ‘How could supplements have been regulated like this?’”
In anticipation of that day, Cohen is working now to nail two more drugs that show up in supplements. He’s also been studying yohimbine, a prescription drug that can be extracted from the bark of a species of West African evergreen tree and sometimes appears in bodybuilding capsules. Like ephedrine, yohimbine “comes from a plant but is pharmaceutically active,” he says, blurring the line between drug and supplement.
His dream is an informed populace, with companies required to fork over the recipes and the risks of their products. “Whenever possible, we should have the freedom of being able to purchase whatever we want to put in our body,” Cohen says. “People should be able to purchase echinacea. It’s just, when they purchase echinacea, they should know what they’re getting.”
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