Product Oversight and Marketing
Dietary Supplement Health and Education Act of 1994 (DSHEA)
Food and Drug Administration (FDA)
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Regulates dietary supplements under separate regulations from those that cover “conventional” foods and drug products (prescription and over-the-counter)
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Under the DSHEA, dietary supplement manufacturers are responsible for ensuring that the product is safe before it is marketed.
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The FDA is responsible for taking action against any unsafe product after it reaches the market.
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Unlike other drugs, manufacturers need not register or get approval from the FDA before producing or selling dietary supplements.
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It is the manufacturer’s responsibility to ensure that product label information is truthful and not misleading; the manufacturer also dictates product purity.
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The FDA has established a Dietary Supplements Guideline in 2007 for current Good Manufacturing Practices (cGMP) for dietary supplements. Established guidelines require that dietary supplements be produced in a quality manner, not contain contaminants or impurities, and have accurate labeling.
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Postmarketing responsibilities of the FDA include monitoring safety (voluntary dietary supplement adverse event [AE] reporting) and inspecting product information (claims, labeling, package inserts, and accompanying literature). These guidelines do not address the underlying safety of the supplement itself and remain nonbinding to the manufacturer.
Federal Trade Commission (FTC)
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Responsible for overseeing truth in dietary supplement advertising
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Requires that claims on products be symptom-specific and not disease-oriented; for example, statements such as “supplement X can stimulate immune system” are acceptable, but statements such as “supplement X can treat, cure, or resolve infections” are not.
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Despite the FTC requirement that claims on products be symptom-specific and not disease-oriented, one study that analyzed internet websites to assess the nature of marketing claims for the eight best-selling herbal products found that this rule is not always followed. The study revealed that most available information is derived from vendor sites and that half of these sites claim that these products can treat, prevent, diagnose, or cure specific diseases. Physicians should be aware that these claims appear on the first page of the most commonly used internet search engines.
Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS)
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The Center for Food Safety and Applied Nutrition (CFSAN) maintains an AE monitoring system known as CAERS.
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The primary reporting system established by the FDA is a voluntary reporting system; according to a report by the Office of the Inspector General, <1% of all AEs are reported through the CAERS.
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Dietary supplements are not evaluated for safety, and manufacturers are not required to prove safety. It is the FDA’s responsibility to prove harmful consequences.
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In 2006, the Dietary Supplement and Nonprescription Act mandated reporting of serious AEs by supplement manufacturers (deaths or life-threatening events, initial hospitalizations or prolongation of stay, disabilities or permanent impairments, and congenital anomalies or birth defects), requiring supplement labels to include the manufacturer’s contact information.
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In 2009, the FDA received only 596 serious and 353 mild or moderate AE reports during a 10-month period in 2008; however, according to the American Association of Poison Control Centers, the estimated annual number of AEs in the United States is closer to 50,000. Therefore, all supplement use should be closely scrutinized in patients who are pregnant or breastfeeding and in children, unless specifically noted.
Other Oversight
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U.S. Pharmacopoeia (USP) has set standards for natural product potency ranges.
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Currently, only 6 brands of dietary supplements have been verified by the USP.
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ConsumerLab ( www.consumerlab.com ) is a helpful site that tests supplements from various companies and reports their potencies.
Marketing
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Since the passage of the DSHEA in 1994, the number of dietary supplements sold in the United States (US) has increased from 4000 to >90,000 in 2014.
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Dietary supplements are estimated to be a US $104 billion industry worldwide (US $30 billion in the US).
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Supplements are marketed to athletes’ fears. Several athletes believe that they have to use supplements to stay equal to competitors or to gain a “competitive edge.” They frequently fear that competitors are using supplements. Over 50% of Olympic-caliber athletes stated that they would take a banned substance if it meant they would win every competition for the next 5 years, even if they would then die from adverse effects of the substance. Among elite athletes, performance differences are minuscule between first- and fourth-place winners; even minor enhancements may mean the difference between victory and defeat.
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Marketing companies rely heavily on testimonials of personal experiences, particularly from famous people and athletes. Many companies successfully sell unproven products using this approach. Supplement manufacturers often sponsor supplement studies, and negative findings may not be published. Word of mouth and hopes to gain a “competitive edge” help fuel sales.
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Sports supplements frequently have no “instant” effects; hence, companies often add stimulants to provide an “energy boost.” Despite a new FDA label law to ensure accuracy in labeling of dietary supplements, there continues to be inaccurate labeling. In an FDA analysis of ephedra supplements, 6–20 other ingredients were identified. Cases have been reported of legal supplements containing trace amounts of illegal supplements. It is truly a “buyer-beware” market ( Box 6.1 ).
Box 6.1
“Buyer-Beware” Information About Supplementation
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Most ergogenic aids lack scientific proof.
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Most supplements have not been adequately tested for efficacy, purity, or safety.
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Be careful of misleading product information.
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“Natural” does not mean safe.
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“More” is seldom better.
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Nothing replaces a well-balanced diet that includes a variety of high-quality foods.
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Athletes use supplements at their own risk.
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Commonly Used Athletic Performance Supplements
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Optimal dose and long-term side effects of most supplements are not known.
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Manufacturers recommend doses and durations that have been tested and claim that side effects apply to these instructions.
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Several athletes may use higher doses than recommended and/or use them for longer periods of time, which raises concerns regarding unknown effects.
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Most supplements try to enhance the normal effects of exercise on the body.
Arginine
Claims: Acutely improve exercise capacity; chronic effects result from stimulation of muscle protein synthesis and anabolism of muscle protein. Soy, sesame, and peanut proteins are an excellent source of arginine.
Mechanism: May promote secretion of endogenous growth hormone (GH); precursor in the synthesis of creatine; augments the production of nitric oxide
Efficacy: The scientific evidence available to support claims of promoting and increasing functional capacity in healthy, athletic participants is limited. Intravenous arginine increases GH, but oral arginine has not shown the same effect. It may increase nitric oxide production, but definitive studies are warranted to confirm the same. Moreover, it significantly increases muscle blood volume but does not affect strength performance. Effects on muscle protein synthesis are likely a net effect in combination with nitric oxide as well as concurrent elevation of other amino acids.
Side effects: None reported in short-duration studies for oral use; occasionally, flushing reported with IV administration
Dosage: 3–9 g/day or 250 mg/kg/day (as used in previous studies)
Bovine Colostrum (BC)
Claims: BC supplementation may increase insulin-like growth factor-1 (IGF-1) levels. May positively influence exercise performance characterized by short bursts of activity; does not improve body composition in elite athletes but shows improvements in nonelite athletes; claims also include increased immune function after exercise
Mechanism : BC stimulates growth factors, including structurally identical IGF-1, which has an anabolic effect and is involved in the regulatory feedback of GH. GH stimulates hepatic production of IGF-1, which in turn provides negative feedback to reduce pituitary production of GH.
Efficacy: Limited studies have shown consistent beneficial effects of BC on recovery and exercise performance and improved immune function in special athletic populations.
Side effects: Occasional minor gastrointestinal (GI) complaints, including flatulence and nausea; a high proportion of participants complain about the “unattractive” taste of the beverage
Dosage: 20–60 g/day
Branched-Chain Amino Acids (BCAAs)
Claims: Important source of energy in prolonged endurance exercise; proposed to increase endurance in long tennis matches, soccer, marathons, long-distance swimming, and cycling activities; may contribute to increased body fat loss and maintenance of a high level of exercise performance; claims to decrease chronic fatigue/overtraining symptoms
Mechanism: Replenishes loss of BCAAs used as fuel, increases protein synthesis and GH secretion, shifts leucine metabolism to fat metabolism, stimulates fat metabolism over glycogen in hypocaloric diets, and prevents decrease in plasma glutamine; inhibits dietary tryptophan transport across the blood–brain barrier, leading to decreased brain serotonin (associated with several brain regions that control central fatigue)
Efficacy: Most studies have reported neither beneficial nor detrimental effects of BCAA; studies on the effects of BCAAs in hypocaloric states are limited. BCAAs have not been shown to reduce chronic fatigue/overtraining symptoms, and preworkout/event BCAA loading has no effect on performance.
Side effects : Fatigue and ergolytic effects have been reported.
Dosage: Usually combined with other amino acids; range: 5–10 g/day (preferably before exercise)
Carbohydrate Supplements
Claims: Used to restore muscle glycogen after exercise, maintain plasma glucose during endurance events (particularly those lasting >90 minutes), and to maximize muscle glycogen before significant glycogen-depleting activities (e.g., marathons or long-course triathlons); various sugars are used, including sucrose, glucose, fructose, and maltodextrin (popular among ultra-endurance athletes).
Mechanism: Increased blood glucose stimulates insulin production and GLUT-4 translocation in muscle, which results in increased glucose uptake and glycogen storage in muscle. Carbohydrates with a high glycemic index increase plasma glucose quickly and serve as a fuel source during sustained exercise.
Efficacy: Mixed reviews for pre-exercise supplementation and carbohydrate loading; benefits of supplementation after exercise and during long events (>90 minutes) are well supported.
Side effects: Individual GI tolerance varies with different types of carbohydrate supplements, and some athletes may experience dyspepsia and GI upset.
Dosage: Before exercise (benefits of carbohydrate loading controversial): 4 g/kg within 3 hours before and 1.1 g/kg 1 hour before; 10 g/kg/day of carbohydrates 3–7 days before a sport event. During exercise: 0.7–1.0 g/hour for events lasting >1 hour; sources include sports drinks (5–10 ounces every 15 minutes), sports gels or candies (2 gels and water), or gummy candy (a handful per hour and water). After exercise: 7–1.0 g/kg every 2 hours for the first 4 hours after exercise (first 90 minutes after exercise is the most important); best if started within 30 minutes of stopping exercise. Use a food source with a high glycemic index; addition of protein to the carbohydrate supplement increases glycogen production.
Chromium
Claims: Trace mineral used for weight loss and for enhancement of glycemic control in the treatment of diabetes; proposed for the treatment of hyperlipidemia and hypercholesterolemia; used by athletes in attempts to gain muscle and lose fat
Mechanism: Functions in carbohydrate, protein, and fat metabolism as a cofactor that enhances action of insulin and uptake of amino acids into muscles; improves lipid profile and is theorized to sensitize insulin receptors in the brain, resulting in appetite suppression and down-regulation of insulin secretion; glycogen synthesis increases in chromium-deficient individuals. Exercise may result in loss of chromium, but athletes conserve chromium and probably do not develop deficiencies.
Efficacy: Possibly effective when used to reduce cholesterol, but probably ineffective for weight loss; mild hypoglycemic effect caused by a mechanism similar to metformin ; considerable scientific evidence indicates that chromium has no effect on body composition when taken in the form of a supplement, and there are serious concerns regarding the potential adverse effects of chromium accumulation within the body, particularly with long-term use
Side effects: Chromium interferes with iron metabolism and zinc absorption. Prolonged use and abuse linked with serious side effects, including anemia, chromosomal damage, cognitive impairment, interstitial nephritis, GI intolerance, tremor, and insomnia; commercial preparations containing ephedrine restricted; low doses of the combined preparation have been found to cause hypertension, stroke, and death
Dosage: Chromium picolinate is more easily absorbed than other forms of chromium; chromium is complexed to picolinate to facilitate absorption. Common dose is 50–200 (mean, 120) mcg/day; similar dosing often found in multivitamins. Lower doses may be safer than higher doses.
Creatine
Probably the most frequently used and most researched supplement consumed by athletes
Claims: Creatine may increase exercise performance in short repetitive bouts of high-intensity exercise offset by brief rest periods (30–120 seconds). Increase in exercise performance and work capacity probably leads to increased muscle mass in some athletes.
Postulated mechanism: Creatine is a low-molecular-weight, complex amino acid endogenously produced primarily in the liver and stored primarily in skeletal muscles. Hydrolysis of creatine phosphate results in rapid production of adenosine triphosphate (ATP), which is needed for muscle contraction. Maximal muscle stores of total creatine may enhance the ATP turnover rate and increase phosphocreatine resynthesis, resulting in shorter recovery periods and overall increased training load (volume/intensity). Creatine depletion is a limiting factor of anaerobic exercise. Free creatine may stimulate protein synthesis and cause muscle hydration, which results in increased muscle mass and strength.
Efficacy: Numerous studies have examined the effects of creatine supplementation on athletic performance. Despite some disagreement, general consensus is that creatine supplementation has a small, but real, beneficial effect on anaerobic activity, specifically during short-duration, repetitive, high-intensity exercises. Does not benefit aerobic training or performance and does not alter maximal force production; data that address chronic creatine supplementation, high-dose supplementation, and supplementation in young athletes are lacking. Reported to increase muscle phosphocreatine content by up to 20%, but this does not mimic physiologic changes related to training; apparently, there are responders and nonresponders to creatine; specifically, vegetarians who do not ingest primary exogenous sources of creatine (meat and fish) may benefit more from creatine supplementation.
Side effects: No serious side effects have been consistently documented from creatine supplementation when used for up to 6 months. Weight gain is a proven side effect, and areas of theoretical concern and anecdotal reports include the following:
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Renal
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Creatine can spontaneously degrade to creatinine, and increases in both urine and serum creatinine levels have been reported. Elevations are likely brief and clinically insignificant.
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Athletes with history of renal dysfunction or diseases that may lead to renal dysfunction (e.g., diabetes) should use creatine with caution.
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Athletes using potentially nephrotoxic drugs (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs]) may be at a higher risk of renal dysfunction.
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Close monitoring of renal function should be considered as long-term effects of creatine on the kidney are unknown.
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Gastrointestinal
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Nausea, bloating, cramping, and diarrhea have been reported by users, but effects are not supported by clinical studies.
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No hepatic dysfunction reported
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Cardiovascular
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The amount of creatine taken up by the myocardium is unknown. Animal studies that report no substantial myocardial uptake also report no skeletal muscle uptake.
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Whether this is detrimental or possibly even beneficial remains unknown.
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Dehydration
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Anecdotal reports of dehydration, particularly in hot, humid conditions; hence, adequate hydration in creatine users encouraged
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May not represent true dehydration because creatine increases total body water proportion, but osmotic properties of creatine may increase third spacing, depleting intravascular fluid volume
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High-dose creatine best avoided during periods of increased thermal stress
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Muscular
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Anecdotal reports mention increased muscle cramping and strains but remains unproven
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Fluid retention that may accompany creatine ingestion, particularly with loading doses, may theoretically increase compartmental pressure and predispose athletes to exertional compartment syndrome
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Dosage: Some experts recommend loading doses of 20–30 g/day (5–7 g four times/day) for 5–7 days (an amount of creatine equal to the amount in 5–6 pounds of beef), followed by doses of 2–4 g/day to maintain intramuscular creatine stores. Other investigators have shown that intramuscular creatine stores reach the same level with a dose of 3 g/day, and these stores are maintained with as little as 2 g/day with no loading phase. Lower doses take longer to attain desired intramuscular creatine levels. Dosing may be based on body weight: loading dose of 0.3 g/kg/day with a maintenance dose of 0.03 g/kg/day. The “more is better” philosophy held by many athletes remains a concern because of the “ceiling” for muscle storage (5 g creatine/kg muscle mass) and excess creatine is not used by the muscles.
Fluid Replacement Beverages
Claims: Used to prevent and treat dehydration; dehydration >3% decreases maximal aerobic power by 5%
Mechanism: Prevents dehydration/hypohydration and associated effects; prevents heat intolerance, maintain stroke volume, cognitive functioning, strength, and work capacity
Efficacy: Numerous studies have reported decreased performance in “hypohydrated” athletes. Recent studies have demonstrated that hypohydration decreases strength.
Side effects: Overhydration may cause hyponatremia, but for hyponatremia to occur, the hydration must be excessive and occur over a long period (e.g., endurance or ultra-endurance events that last >4 hours). GI upset may occur, particularly with fructose-containing fluid replacement drinks.
Dosage: American College of Sports Medicine recommends consumption of 400–600 mL of water 2 hours before exercise and 150–300 mL every 15–20 minutes of exercise. Additional consumption is needed in climates associated with high sweat rates. Drinking to thirst important; can also monitor urine color and volume and body weight (BW). Addition of carbohydrates is recommended for activities lasting >90 minutes. Hydration after exercise is also important. For athletes who need rapid recovery from dehydration, it is recommended to drink 1.5 L/kg of BW lost during exercise.
Beta-Hydroxy Beta-Methylbutyrate (HMB)
Claims: Regulate protein metabolism, decreasing catabolism, increasing lean muscle mass and strength; often used to enhance esthetic and physical appearance in bodybuilding
Mechanism: Exact mechanism unknown; HMB is a metabolite of leucine, a BCAA, and may regulate enzymes responsible for protein breakdown, inhibiting breakdown of muscle during and after vigorous activity. HMB in liver and muscle cells is metabolized to HMG-CoA, which is then used in the synthesis of cholesterol, which increases the availability of cholesterol for cell wall synthesis. Localized deficiency of cholesterol for cell wall synthesis is postulated as a restriction to muscle hypertrophy, and increased local cholesterol stores could theoretically relieve this restriction. HMB may also undergo polymerization, stabilizing the cell membrane as it may be used as a structural component. Also proposed to increase muscle cell fatty-acid oxidation through unknown mechanisms and lead to a decrease in fat mass
Efficacy: Few scientific investigations published; may have additive effects when combined with creatine; studies have demonstrated certain benefits in untrained athletes but no significant improvement in trained athletes.
Side effects: No reported side effects, but research seems inadequate
Dosage: 1.5 g administered 1–3 times daily (2–3 g/day) in clinical trials
Carnitine
Claims: Increase aerobic and anaerobic capacity and promote fat loss
Mechanism: Increases long-chain fatty acid oxidation in skeletal muscles during exercise
Efficacy: Clinical trials inconclusive and suffer from design limitations; small-scale studies have reported no alteration in L-carnitine levels in muscles following supplementation or after a single prolonged exercise session. Twenty years of research revealed no consistent evidence that carnitine supplements can improve exercise or physical performance in healthy individuals.
Side effects: Nausea, vomiting, abdominal cramps, diarrhea, and a “fishy” body odor; rare side effects include muscle weakness in uremic patients and seizures in individuals with known seizure disorder.
Dosage: 2–6 g/day in 2–3 doses with meals
L-Glutamine
Claims: L-glutamine is the most abundant amino acid in the body. Is used in treatment of wound healing, immune function, and chemotherapy-induced stomatitis; athletes use it to prevent impaired immune responses following prolonged exercise.
Mechanism: Originally classified as a nonessential amino acid, glutamine is now considered essential for maintaining intestinal function, immune response, and amino acid homeostasis during times of stress. Is an important fuel for cells of the immune system (lymphocytes and macrophages); during prolonged exercise, as in other forms of chronic stress, plasma glutamine may decrease. Muscle glutamine may drop in an effort to sustain an anabolic state; if glutamine drops below critical levels, athletes may revert to a catabolic state.
Efficacy: Human and animal studies have reported conflicting results. Lack of reliable data for most proposed uses; preliminary data suggest that glutamine supplementation may enhance immune function. Glutamine has been shown to reduce upper respiratory infections in athletes after vigorous exercise, but additional research is warranted to confirm this finding. May be effective in treating chemotherapy-induced stomatitis
Side effects: No significant adverse reactions reported; may be safe at appropriate doses; occasional GI upset reported
Dosage: Typical dose: 20–30 g/day; tolerated without side effects at doses up to 40 g/day
Nitric Oxide (NO)
Claims: Nitric oxide (NO) thought to increase muscular strength and endurance; has been shown to be beneficial in patients with cardiac disease and endothelial dysfunction; marketed to athletes with claim that vasodilation associated with NO improves muscular vascular perfusion and that increase in blood flow improves muscular gains with resistance training
Mechanism : Nitric oxide (NO) is produced in the body by an enzyme called nitric oxide synthase , which converts the amino acid L-arginine to nitric oxide and L-citrulline. Acts through vasodilatation, facilitating blood flow to muscle cells; also bactericidal, released by macrophages; a combination of these two effects observed in septic shock
Efficacy: Small subject numbers and lack of standardization of previous activity levels make current studies inconclusive.
Side effects: None identified in short-term studies
Dosage: Supplements rely on the conversion of an intermediate to NO, most often arginine, typically used at 3–6 g/day
Protein Supplements
Claims: Protein supplementation above American Dietetic Association (ADA) recommendations (0.8 g/kg/day) is used to prevent negative nitrogen balance and to aid protein synthesis, particularly during high-intensity exercise. Numerous athletes, particularly weight lifters, use protein supplements to “bulk up” or to add muscle mass. Most frequently used varieties include whey, soy, or egg whites.
Mechanism: Protein supplements aid synthesis of new muscle proteins. Whey protein is a good source of BCAAs, which were discussed previously.
Efficacy: Whey protein is a soluble, easy-to-digest protein. Most studies show change in muscle synthesis with increased protein intake, but subjects were not tested for increased strength. Athletes require more protein than nonathletes (see Chapter 5 : Sports Nutrition), and protein supplements may be used as dietary adjuncts.
Side effects: None documented at doses up to 2 g/kg/day in healthy individuals, but sustained use at this level is concerning. Caution recommended in athletes with renal insufficiency or failure as well as in individuals with lactose or dairy protein allergies; excessive protein intake stored as fat
Dosage: Recommended dose for recreational athletes is 0.8–1.0 g/kg/day, for endurance athletes is 1.2–1.4 g/kg/day, and for strength-trained individuals, 1.6–1.7 g/kg/day.
Ribose
Claim: Several roles in human physiology; necessary substrate for synthesis of nucleotides and is a part of the building blocks that form DNA and RNA molecules; claims that it increases synthesis and reformation of ATP, improves high-power performance as well as recovery and muscle growth, and quickly restores energy levels in heart and skeletal muscles
Mechanism: Structural component of ATP, which is the primary energy source for exercising muscle; during intense muscular activity, total amount of available ATP is quickly depleted; estimated to take approximately 3 days to restore ATP levels to baseline; ribose helps to restore the level of adenosine nucleotides, and supplementation has been shown to increase the rate of ATP resynthesis following intense exercise.
Efficacy: Studies for various sports performance parameters; most evaluate effects on anaerobic cycle sprints, with limited studies on strength and endurance. Consistent ergogenic benefit not identified
Side effects: Headache, nausea, hyperuricemia, and hyperuricosuria; doses >200 mg/kg/h may cause diarrhea. Precautions should be taken with ribose and diabetes because all simple sugars increase insulin levels . Supplementation may cause hypoglycemia in patients with diabetes
Dosage : 5–10 g/day, but markedly different ribose dosages have been used in studies. Lack of consensus on recommended dose of ribose
Tribulus Terrestris
Claim: Herb claimed to “naturally” increase testosterone levels
Mechanism: Postulated to increase release of luteinizing hormone (LH), indirectly stimulating testosterone release
Efficacy: Studies do not support claims of improved body composition or athletic performance. Elevation of serum testosterone may have anabolic effects.
Side effects: No reported side effects in humans; photosensitivity has been reported in animals grazing on tribulus terrestris. Potential anabolic side effects if it elevates testosterone
Dosage: 500–650 mg tablets for once-daily dosing frequently recommended; often combined with other “prohormones”
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