October 2009 Issue

Dietary Supplement Quality and Safety
By Ellen Coleman, MA, MPH, RD, CSSD
Today’s Dietitian
Vol. 11 No. 10 P. 56

Suggested CDR Learning Codes: 2000, 3000, 3020, 4000, 6000, 6010; Level 2

The headlines are worrisome: “Prescription Drugs Found in Weight Loss Supplements”; “Sex Enhancers Contain Drugs”; “Steroids in Musclebuilder Supplements.” The details are worse: A popular weight loss supplement is recalled due to reports of liver injury; one out of four supplements tested by an independent laboratory lacks the promised ingredients or has other serious problems.

These are some recent incidents that have raised concerns regarding the quality and safety of dietary supplements. The supplement trade publication Nutrition Business Journal placed the total sales of dietary supplements at $23.7 billion in 2007, with about $1.7 billion for weight loss supplements and $2.5 billion for sports supplements. With many people focused on obesity prevention and weight reduction and many young people convinced that they need supplements to compete in sports, these amounts will likely increase. Clearly, dietitians and their clients should be concerned with supplement safety and effectiveness. This article will help professionals define the issues and will provide some examples of dangerously contaminated supplements.

Tainted Weight Loss Supplements
In December 2008, the FDA alerted consumers that certain weight loss supplements contained active pharmaceutical ingredients. The FDA expanded this alert in January and March 2009, identifying more than 70 products that may be harmful.1 Laboratory tests conducted by the FDA revealed the presence of sibutramine, fenproporex, phenytoin, bumetanide, furosemide, fluoxetine, phenolphthalein, rimonabant, and cetilistat.1

• Sibutramine is a schedule IV controlled substance and the active ingredient in Meridia, an approved prescription drug for the treatment of obesity. Some of the weight loss supplements suggested taking more than three times the recommended daily dosage of sibutramine.

• Fenproporex is an amphetamine derivative not approved for weight loss use in the United States. It is a class IV controlled substance that can cause an individual to test positive for amphetamines via urinalysis.

• Phenytoin is the active ingredient in Dilantin, a prescription antiseizure drug.1

• Bumetanide is the active ingredient in Bumex, a prescription diuretic. Bumex carries a “black box warning” because the drug may lead to serious and significant fluid and electrolyte loss. (A black box warning, sometimes called a black label warning or boxed warning, is a type of warning that appears on the package or insert for prescription drugs that may cause serious adverse effects. It is so named for the black border that usually surrounds the text of the warning.)

• Furosemide is the active ingredient in Lasix, a potent diuretic. It can cause profound dehydration and electrolyte imbalance.1

• Fluoxetine is the active ingredient in Prozac, a prescription antidepressant. Prozac carries a boxed warning, as antidepressants can increase the risk of suicidal thoughts and suicide.

• Phenolphthalein was an ingredient in some over-the-counter laxative products until 1999, when studies indicated it may be carcinogenic and mutagenic.

• Rimonabant is the active ingredient in Zimulti (known in Europe as Acomplia) but is not approved for use in the United States.1

• Cetilistat is an experimental obesity drug that decreases fat absorption and is currently the subject of clinical trials.1

Undeclared prescription drugs in weight loss supplements can cause serious adverse effects when used alone and may have dangerous interactions with drugs that the consumer already takes.1

While these tainted products generally do not list the manufacturer on the label or in advertisements, most appear to have been manufactured in China.1 The FDA is currently seeking recalls of these products and may take additional enforcement actions, including warning letters, seizure, injunction, or criminal charges. However, the FDA notes that it cannot test and identify all weight loss products on the market that have potentially dangerous contaminants and further indicates that enforcement actions and consumer advisories cover only a small number of the potentially harmful weight loss products marketed to consumers on the Internet and at some retail stores.1

Tainted Sexual Enhancement Supplements
In July 2009, the Nature & Health Company issued a voluntary nationwide recall for six male enhancement supplements sold under the names LibieXtreme, Y-4ever, Libimax X Liquid, Powermania (Liquid and Capsule), and Herbal Disiac. The FDA found that these supplements contained either tadalafil (an ingredient of the prescription drug Cialis, approved for the treatment of erectile dysfunction), its analog aminotadalafil, or the analog of sildenafil (an ingredient of the prescription drug Viagra, also approved for the treatment of erectile dysfunction). None of the active drug ingredients were listed on the product labels.

In July 2008, EG Labs, LLC conducted a nationwide voluntary recall of the company’s supplement sold under the name Viapro. The FDA found that the supplement contained thiomethisosildenafil, an analog of sildenafil. Also that month, Jack Distribution, LLC issued a voluntary nationwide recall of all lot numbers of the company’s supplements sold under the brand names Rize 2 The Occasion and Rose 4 Her. The FDA determined that they also contained thiomethisosildenafil.

In May 2008, International Pharmaceuticals, Ltd issued a nationwide voluntary recall of its supplement sold under the name Viril-Ity-Power. The FDA found that the supplement contained hydroxyhomosildenafil, an analog of sildenafil.

In March 2008, the FDA advised consumers not to purchase the dietary supplements Blue Steel or Hero, as they contained substances similar to sildenafil.

In February 2008, Palo Alto Labs conducted a nationwide voluntary recall of its supplements sold under the name Aspire36 and Aspire Lite. The FDA determined that the supplements contained sulfoaildenafil, an analog of sildenafil.

In November 2007, American True Man Health Inc issued a nationwide voluntary recall of its supplements sold under the names True Man’s Sexual Energy Nutriment Men’s Formula, Energy Max, and Energy Supplement Men’s Formula. The FDA found that the supplements contained an analog resembling the active ingredients in tadalafil, vardenafil (an ingredient of the prescription drug Levitra, approved for the treatment of erectile dysfunction), and sildenafil.

In March 2007, Jen-On Herbal Science International, Inc issued a nationwide voluntary recall of its supplement sold under the name H S Joy of Love. The FDA found that the supplement contained piperadino vardenafil, an analog of vardenafil. Also that month, Barodon SF conducted a nationwide voluntary recall of its supplement sold under the name V.MAX. The FDA determined that the supplement contained aminotadalafil, an analog of tadalafil.

In July 2006, the FDA warned consumers not to purchase the dietary supplements Zimaxx, Libidus, Neophase, Nasutra, Vigor-25, Actra-Rx, or 4EVERON. Chemical analysis by the FDA revealed that Zimaxx contained sildenafil, while the other products contained analogs of either sildenafil or vardenafil.

In November 2004, the FDA warned consumers not to purchase the dietary supplements Actra-Rx or Yilishen, as they contained prescription-strength sildenafil.

In May 2003, Best Life International warned consumers not to take its product known as Viga, as it contained sildenafil. In the month before, Ultra Health Laboratories, Inc and Bionate International, Inc warned consumers not to consume the product known as Vinarol, as it contained sildenafil.

Some companies have been uncooperative in recalling tainted products. In 2008, the FDA announced that U.S. Marshals seized products from two different firms that contained undeclared ingredients found in FDA-approved prescription drugs for the treatment of erectile dysfunction.2 In April 2008, authorities seized more than 14,000 dosages of products known as Shangai Regular, Shangai Ultra, Super Shangai, Naturalë Super Plus, and Lady Shangai. The seized products were valued at more than $100,000, originated in China, and were packaged and distributed by Shangai Distributors, Inc of Coamo, Puerto Rico.2 In December 2007, the FDA had recommended that consumers not use these products, as they contained sildenafil or a sildenafil analog.

In July 2008, U.S. Marshals seized nearly $74,000 worth of Xiadafil VIP tablets distributed by SEI Pharmaceuticals, Inc of Miami.2 The FDA made a formal request to the company in May 2008 to recall the product after laboratory analysis revealed that it contained hydroxyhomosildenafil.

In both cases, the firms prompted FDA enforcement by failing to act after being notified of the potential adverse health risks that the products posed.2

The undisclosed presence of prescription drugs for erectile dysfunction (and their analogs) can lead to serious adverse effects, as the product may interact with prescription drugs containing nitrates and lower blood pressure to unsafe levels. People with diabetes, high blood pressure, high cholesterol, or heart disease are often prescribed nitrates, and men with these conditions commonly suffer from erectile dysfunction.2 The FDA has identified at least 29 products that contain potentially harmful prescription drugs.2

The FDA has found that many of these products or their active ingredients are imported into the United States and is working closely with U.S. Customs and Border Protection to effectively screen and stop these shipments from entering the country. Follow-up investigations continue to identify numerous problem products, resulting in additional enforcement actions to protect consumers. The FDA is also seeking creative ways to educate consumers about the risks of buying sexual enhancement products and other drugs online.2

Tainted Muscle-Building Supplements
Some apparently “harmless” supplements contain ingredients that aren’t declared on the label but are prohibited by the doping regulations of the National Collegiate Athletic Association, the International Olympic Committee (IOC), and the World Anti-Doping Agency. As a result, an unsuspecting athlete who places too much trust in the supplement label may test positive for banned substances.3

Contaminants that have been identified include a variety of anabolic androgenic steroids (including testosterone and nandrolone, as well as the prohormones of these compounds) and ephedrine.3 There are several ways in which supplement use can cause an athlete to unintentionally test positive for doping. In most cases, the contamination occurs during the production process due to poor manufacturing practices. However, there is also evidence of deliberate adulteration of products by manufacturers.3

In 2002, the IOC Medical Commission found that of 634 nonhormonal nutritional supplements tested from 13 different countries, 94 (14.8%) contained substances that would have led to a positive doping test but weren’t listed on any label. Of these 94 samples, 23 contained compounds that could be metabolized to either nandrolone or testosterone, 64 contained substances that could have been metabolized to testosterone, and seven contained precursors of nandrolone alone. Most of the positive supplements were bought in the Netherlands (25.8%), Austria (22.7%), the United Kingdom (18.8%), and the United States (18.8%). Twenty-one percent of the nutritional supplements from prohormone-selling companies contained anabolic androgenic steroids, whereas 9.6% of the supplements from companies not selling prohormones were positive for containing steroids.4

According to a 2007 study, 13 of 52 supplements (25%) purchased at various U.S. retailers contained small amounts of steroids and six (11.5%) had banned stimulants.5 The study was conducted by Informed-Choice, a nonprofit coalition of supplement companies, and HFL, an antidoping laboratory located in England. The highest incidence of contamination appeared to be in the testosterone-booster product category. Six of the nine products (67%) in this category (including product “stacks,” which contained a testosterone-booster component) contained steroids and/or stimulants as contaminants. The second-highest predominance of contamination was found in weight loss products, with 29% of products tested (including stacks) containing steroid and/or stimulant contamination. The third-highest incidence of contamination was found in muscle-building products. In this category (including stacks that contained muscle-building components), 24% contained steroid and/or stimulant contaminants.5

Swiss researchers found that three supplements purchased on the Internet contained very high amounts of the anabolic steroid metandienone. One creatine product and three “mental enhancers” contained traces of hormones or prohormones not declared on the labels. Fourteen prohormone products contained substances other than those that the manufacturer indicated.6 Italian researchers found that 12.5% of 64 nutritional supplements contained banned substances (anabolic steroids and ephedrine) not declared on the label.7

The principle of strict liability that applies in sports means that innocent ingestion of prohibited substances is not an acceptable excuse. Athletes who test positive are legally responsible and subject to penalties. Although some athletes are guilty of deliberate cheating, a few positive tests are likely the result of inadvertent ingestion of prohibited substances present in otherwise innocuous dietary supplements.3

Some tainted supplements even contain designer steroids such as desoxymethyltestosterone (DMT, or Madol), which was first identified six years ago during the investigation into the Bay Area Laboratory Co-Operative. In November 2005, The Washington Post announced that the supplement Halodrol-50 contained DMT and a steroid similar to Oral-Turinabol, the principal steroid in the former East Germany’s secret sports doping program.

In July, The New York Times reported that the supplements Tren Xtreme and Mass Extreme contained DMT and other designer steroids. Consumers who used the products have reported severe liver and kidney problems.

There are known health risks associated with the use of anabolic steroids such as testosterone. However, unknowingly taking supplements that contain illegal designer steroids is extremely dangerous and involves unknown risks because these drugs have not been studied for safety.

Hydroxycut Product Recall
In May, the FDA warned consumers to immediately stop using Hydroxycut products by Iovate Health Sciences, Inc due to a number of serious liver injuries. Iovate agreed to recall the products, which were marketed as weight-control, fat-burner, and energy-enhancer supplements. The FDA received 23 reports of serious liver injury, including jaundice, elevated liver enzymes, and severe liver damage requiring a liver transplant; one death due to liver failure was reported. Other reported health problems included seizures, cardiovascular disorders, and rhabdomyolysis. All of these adverse effects occurred at Hydroxycut’s recommended doses.8           

The FDA has not yet determined which Hydroxycut ingredients or dosages may be associated with liver toxicity and other adverse effects. Other health-related factors may be important. The Hydroxycut products contained a variety of ingredients and herbal extracts and the formulation has changed over time. Hydroxycut Cleanse and Hoodia products are not affected by the recall.

Supplement Quality Problems
According to the independent testing firm ConsumerLab, about one in four dietary supplements tested does not meet quality or safety standards. Some supplements are tainted with pesticides, salmonella, glass, bacteria, or heavy metals such as lead and cadmium. Others fail testing due to lacking ingredients, improper ingredients, failure to break down properly, and/or mislabeling. Some of the tainted products contain ingredients from China because manufacturers seek low-cost ingredients.

Multivitamins and multiminerals are America’s most popular dietary supplements. Since they contain multiple ingredients, they are among those supplements most likely to have quality-control problems. Nearly one third of the multivitamins tested (10 products) contained significantly more or less ingredients than the label claimed or were contaminated with lead. In addition, several products (including three for children) exceeded tolerable limits established by the Institute of Medicine for nutrients such as vitamin A, folic acid, niacin, and zinc, according to ConsumerLab.

Of the seven ginkgo products that ConsumerLab selected for review, five failed to pass testing. Only 75% of magnesium supplements that ConsumerLab selected for review passed quality standards. Among the 21 joint health supplements (glucosamine, chondroitin, and/or methylsulfonylmethane) ConsumerLab selected and tested, only 16 met quality standards and FDA labeling requirements. Of the green tea and selenium supplements ConsumerLab selected and tested, 40% failed testing. Among the 13 probiotic products that ConsumerLab selected and tested, only eight were found to contain at least 1 billion organisms per daily dose (a generally recommended minimum).

Supplement Regulation
Under the 1994 Dietary Supplement Health and Education Act, dietary supplements are generally presumed to be safe. The FDA does not have the authority to require supplements to be approved for safety and efficacy before they enter the market, as it does for drugs.9

The FDA relies primarily on postmarket surveillance efforts (monitoring adverse event reports, reviewing consumer complaints, and conducting facility inspections) to identify potential safety concerns related to supplements. When a safety concern is identified, the FDA must demonstrate that the supplement presents a significant or unreasonable risk, or is otherwise adulterated, before it can be removed from the market.9

In a recent report, the Government Accountability Office (GAO) indicates that this regulatory approach falls short in protecting U.S. consumers. Although the FDA successfully banned supplements containing ephedrine alkaloids (ephedra) in 2004, the ban became effective only after the FDA had received thousands of reports of adverse events, including a number of deaths, 10 years after the agency issued its first advisory.9
Since ephedra was banned, several positive changes have occurred in the regulation of dietary supplements. The Dietary Supplement and Nonprescription Drug Consumer Protection Act requires companies that receive a serious adverse event report to submit this information to the FDA. The act took effect in December 2007 and was passed in response to concerns about how difficult it was for the FDA to ban ephedra sales, even though thousands of people had adverse effects.9

Serious adverse events include any health-related events that cause death, a life-threatening incident, an inpatient hospitalization, or a birth defect or that require a medical or surgical intervention to prevent these serious outcomes. The act does not require companies to report moderate or mild adverse events (eg, gastrointestinal distress, headaches), but companies may do so voluntarily. In addition, healthcare practitioners and consumers can submit voluntary reports of serious, moderate, and mild adverse events.9

In June 2007, the FDA established regulations requiring Current Good Manufacturing Practices for supplements.10 These regulations describe the conditions under which supplements must be manufactured, packaged, labeled, and stored. The Current Good Manufacturing Practices are being implemented in phases (based on company size) and will be in full effect by 2010. The goal is to prevent the inclusion of the wrong ingredients, too much or too little of an ingredient, any contamination by substances (eg, natural toxins, bacteria, pesticides, glass, lead and other heavy metals), and improper packaging and labeling.10

Regulatory Problems
Although the FDA has taken steps to identify and act on supplement safety concerns, several factors limit the agency’s oversight. The FDA has inadequate information regarding the number and location of supplement companies, the identity and ingredients of supplements currently available, and any mild or moderate adverse events reported to industry.  (Reporting is only mandatory for serious adverse events). The FDA also allocates few resources to dietary supplement oversight activities compared with other FDA-regulated products. Moreover, since the FDA lacks mandatory recall authority, its ability to efficiently and effectively remove a product from the market is restricted, even when it discovers a safety concern. Banning an unsafe ingredient is also difficult because the agency must demonstrate that the supplement poses a significant or unreasonable risk or is otherwise adulterated. Thus, consumers remain vulnerable to risks posed by potentially unsafe products.9

The GAO report notes that consumers are not well informed about dietary supplements, may not be aware of potential side effects of supplements, and may not consider a dietary supplement as a possible factor when experiencing an adverse reaction. Weaknesses in the regulatory system increase the chance of unsafe products reaching the market and poor consumer knowledge increases the potential health risks associated with supplement use.9

To enhance FDA oversight of supplements and improve consumer understanding, the GAO recommends that the secretary of Health and Human Services direct the commissioner of the FDA to do the following:

• require supplement companies to identify themselves, provide a list and copy of labels of all supplements they sell, update this information annually, and report all adverse events to the FDA;

• provide guidance for industry on what constitutes a new dietary ingredient, evidence needed to document the safety of new dietary ingredients, and appropriate methods to establish ingredient identity;

• clarify for industry when products should be marketed as either supplements or conventional foods formulated with added ingredients; and

• increase consumer outreach and identify additional methods to educate consumers about supplement safety, efficacy, and labeling; implement these methods; and determine their effectiveness.

Summary
With new products being created, introduced, and marketed at a furious pace, it is incumbent upon dietitians to understand that their clients using certain weight loss, sexual enhancement, and muscle-building supplements may be at risk from undeclared active pharmaceutical ingredients and that about 25% of dietary supplements tested do not meet quality or safety standards. Further, RDs should stress that certain factors limit regulatory agencies’ oversight abilities and that weaknesses in the regulatory system increase the chance of unsafe products reaching the market.

It remains to be seen whether the GAO recommendations to improve regulation are followed. Until the situation improves, dietitians should stay informed and establish a bond of trust between themselves and their clients. Since many people take supplements because of a perceived deficiency or flaw, they may not feel comfortable revealing their use to an “authority figure” who they feel may disapprove. Developing expertise and speaking knowledgeably about the dangers of some supplements can save a client’s life.

— Ellen Coleman, MA, MPH, RD, CSSD, is a nutrition consultant at The SPORT Clinic in Riverside, Calif.

References
1. U.S. Food and Drug Administration. Questions and answers about FDA’s initiative against contaminated weight loss products. Last updated April 30, 2009. Available at: http://www.fda.gov/Drugs/ResourcesForYou/Consumers/QuestionsAnswers/ucm136187.htm

2. U.S. Food and Drug Administration Consumer Health Information. Hidden risks of erectile dysfunction “treatments” sold online. February 21, 2009. Available at: http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM143726.pdf

3. Maughan RJ. Contamination of dietary supplements and positive drug tests in sport. J Sports Sci. 2005;23(9):883-889.

4. Geyer H, Parr MK, Mareck U, et al. Analysis of non-hormonal nutritional supplements for anabolic-androgenic steroids - results of an international study. Int J Sports Med. 2004;25(2):124-129.

5. Judkins C, Hall D, Hoffman K. Investigation into supplement contamination levels in the US market. HFL. 2007. Available at: http://www.usatoday.com/sports/hfl-supplement-research-report.pdf

6. Baume N, Mahler N, Kamber M, Mangin P, Saugy M. Research of stimulants and anabolic steroids in dietary supplements. Scand J Med Sci Sports. 2006;16(1):41-48.

7. Martello S, Felli M, Chiarotti M. Survey of nutritional supplements for selected illegal anabolic steroids and ephedrine using LC-MS/MS and GC-MS methods, respectively. Food Addit Contam. 2007;24(3):258-265.

8. U.S. Food and Drug Administration Consumer Health Information. Warning on Hydroxycut products. May 1, 2009. Available at: http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM152222.pdf

9. U.S. Government Accountability Office. Dietary supplements: FDA should take further actions to improve oversight and consumer understanding. January 2009. GAO-09-250. Available at: http://www.gao.gov/new.items/d09250.pdf

10. U.S. Food and Drug Administration. FDA issues dietary supplements final rule. June 22, 2007. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108938.htm

Learning Objectives
After completing this continuing education exercise, the learner should be able to:

1. List two prescription drugs found in certain sexual enhancement supplements.
2. List two prescription drugs found in certain weight loss supplements.
3. List two steroids found in muscle-building supplements.
4. Indicate three reasons why supplements have failed testing by ConsumerLab.
5. List two factors that limit the FDA’s oversight of dietary supplements.

Examination
1. Nutrition Business Journal placed the total sales of dietary supplements at _____ billion in 2007.
a. $26.7
b. $23.7
c. $20.7
d. $17.7
e. None of the above

2. The following statement(s) is (are) true about dietary supplements:
a. Dietary supplements do not undergo premarket testing for safety and effectiveness.
b. The amount of active ingredients may be higher or lower than the amount listed on the product label.
c. Products containing “natural” ingredients are safe.
d. a and c
e. a and b

3. The FDA has alerted consumers that certain weight loss supplements contained:
a. sibutramine and bumetanide.
b. fluoxetine and furosemide.
c. tadalafil and sildenafil.
d. a and b
e. a and c

4. The FDA has alerted consumers that certain sexual enhancement supplements contained:
a. rimonabant and cetilistat.
b. vardenafil and sildenafil.
c. phenytoin and phenolphthalein.
d. sibutramine and fluoxetine.
e. None of the above

5. In May, the FDA warned consumers to immediately stop using Hydroxycut products due to a number of serious _______ injuries.
a. kidney
b. heart
c. liver
d. brain
e. None of the above

6. In the study conducted by Informed-Choice and HFL, the highest incidence of contamination appeared to be in:
a. weight loss products.
b. testosterone-booster products.
c. muscle-building products.
d. mental-enhancer products.
e. skin-refresher products.

7. According to the independent testing firm ConsumerLab, about _____ dietary supplements tested do not meet quality or safety standards.
a. one in two
b. one in three
c. one in four
d. one in five
e. one in 10

8. Which statement about supplements and positive drug tests is false?
a. Contamination may occur during the production process due to poor manufacturing practices.
b. Innocent ingestion of prohibited substances through supplements is an acceptable excuse for sports governing authorities.
c. There is evidence of deliberate adulteration of products by manufacturers.
d. Contaminants have included anabolic androgenic steroids and ephedrine.
e. None of the above

9. According to the independent testing firm ConsumerLab, supplements fail testing due to:
a. contamination.
b. a lack of ingredients or improper ingredients.
c. failure to break down properly.
d. mislabeling.
e. All of the above

10. The Government Accountability Office report found that the FDA:
a. has inadequate information about supplement companies and supplements currently available.
b. allocates few resources to dietary supplement oversight.
c. lacks mandatory recall authority.
d. has adequate regulatory authority to keep unsafe supplements from reaching the market.
e. a, b, and c