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healthcare information and
May 2001; Volume 1; 1-12
By Dónal P. O’Mathúna, PhD
Peer-reviewed by David Schiedermayer, MD, FACP
Note to Readers
American Health Consultants is pleased to introduce a new quarterly addition to Alternative Medicine Alert: Alternative Medicine Reports, edited by David Schiedermayer, MD, FACP, Professor of Medicine at the Medical College of Wisconsin in Milwaukee. These monograph-style articles will cover a variety of complementary and alternative therapies for a specific indication. We would like to hear your feedback on this new feature. Please contact Leslie Coplin at (404) 262-5534 or e-mail: email@example.com.
Athletes go to great lengths to promote their health. they train hard, eat carefully balanced meals, rest adequately, seek medical attention for even minor injuries, and purchase expensive gear to minimize injuries. Sometimes, however, they will ingest large amounts of supplements of unknown quality and questionable efficacy in an attempt to enhance their performances. Of the estimated $12 billion in annual sales of dietary supplements, $800 million are for sports supplements.1 Concerned with athletes’ health and fairness in competition, various sporting bodies have stepped into the arena by banning particular substances. Athletes do need to be protected from themselves: In 1997, Sports Illustrated asked almost 200 current or aspiring U.S. Olympic athletes if they would take a drug that would make it possible for them to be world champions for five years even though the drug would then kill them.2 More than half said they’d take it!
Herein lies one of the major concerns with dietary supplements for athletes, and why physicians need a general understanding of the supplements athletes may be using. The pressure to win and perform at one’s peak is intensifying among younger athletes. Parents invest thousands of dollars and hundreds of hours in youngsters who compete for traveling teams. On the line is prestige, a college scholarship, a spot in the limelight as an Olympic athlete, or maybe even huge amounts of money as a professional athlete. Given all these payoffs, all this pressure, why not take supplements?
Physicians need to be familiar with the main supplements being used, what evidence supports their effectiveness and safety, and what is known about their impact on adolescents. When athletes come to your office, either for general health issues or problems related to their training or their supplements, it is important to be knowledgeable about the major supplements they may be using. This familiarity will help set the scene for a professional relationship in which athletes are willing to listen to your advice regarding performance-enhancing supplements.
Dietary supplements taken to improve the energy efficiency and performance of athletes are called ergogenic aids. This review will divide these supplements into three main categories: nutritional, steroidal, and herbal ergogenic aids. Most of the nutritional ergogenic aids are found in a well-balanced diet or produced during normal metabolism, but are taken as supplements in the hope they will further enhance performance. Steroids usually are taken to improve the body’s ability to develop muscle mass and recover from intense training so that better performances result. Herbs constitute another diverse group of plant products taken for a variety of ergogenic reasons.
Nutritional Ergogenic Aids
The motivation behind the use of all nutritional ergogenic aids is a desire to get more energy from the fuels consumed in the diet. It is assumed that the athlete is eating a balanced diet, is consuming necessary vitamins and minerals, and is appropriately hydrated and rested. Training and practice take care of the fitness and skill levels needed. Given the athlete’s genetic endowment, nutritional ergogenic aids attempt to release more energy to fuel exercise or increase the efficiency of the body’s use of that energy.
To understand the reasoning behind the use of many nutritional ergogenic aids, one must understand the basic biochemistry of how cells provide and use energy. The promotional materials used to market these supplements to athletes often include references to related biochemistry. Informed physicians can help athletes and their families understand this information, and spot errors and exaggerated claims. Just because the body’s cells use a particular substance, taking it in supplemental form does not necessarily mean the substance will reach those cells. Even if it does get to the cells, it will not necessarily lead to improved performances. Since the body’s biochemical reactions are intricately interwoven and counter- balanced, an excess of one metabolite may unbalance other reactions leading to undesirable effects. In addition, there are concerns with the quality of supplements available on the U.S. market, which will be described in detail in the discussion of individual supplements.
The chemical energy compound used by all cells is adenosine triphosphate (ATP). Cells store ATP much like a biochemical battery. And just like regular batteries, they get run down and have to be recharged. Muscles store only enough ATP to fuel exercise for a few seconds. More ATP must then be regenerated using phosphate that comes from creatine phosphate (CP), as shown in Figure 1. Even this adds only enough energy for a few more seconds.3 This system fuels up to 10 seconds of activity, and is thus most important in short, intense bursts of activity.
|The role of creatine, phosphate, and ATP in exercise|
After the initial few seconds of exercise, additional energy must be provided by the more familiar metabolic fuels: carbohydrates, fats, and proteins. The first fuel used is glucose, which is released from its storage form, glycogen, contained in both muscle and liver. The glucose is broken down metabolically in the muscle cells after a few seconds of exercise. This process is called glycolysis and results in pyruvate (or pyruvic acid), plus a relatively small amount of ATP. To release the remaining energy from pyruvate, two processes can occur. (See Figure 2.)
|Energy production in a cell|
If athletes are breathing in sufficient oxygen (which requires that they not be exercising too intensely), pyruvate is broken down completely to carbon dioxide, water, and lots of ATP, in a process called aerobic glycolysis. But if the exercise intensifies to where the athlete cannot breath in sufficient oxygen to keep up with energy demands, anaerobic glycolysis kicks in. Some ATP is produced, but only enough to allow intense exercise for 30 seconds to two minutes. After this, the accumulation of lactic acid and accompanying acidosis cause fatigue to set in rapidly. The precise length of time is influenced by training since exercise results in metabolic changes that improve fitness, not just muscular and cardiovascular changes.
Aerobic glycolysis can sustain exercise for a few hours, though only if the intensity is not very demanding. During this time, pyruvate is broken down in the presence of oxygen via reactions called the citric acid cycle (CAC in Figure 2; also known as the Krebs cycle). In addition to producing ATP directly, aerobic glycolysis produces another compound called nicotinamide adenine dinucleotide (NADH). After NADH is processed through another metabolic system called the electron transport chain (ETC in Figure 2), more ATP is produced.
Endurance athletes use aerobic glycolysis to metabolize stored carbohydrates, but stored fat is a more abundant source of fuel. An athlete’s body stores much more fat than carbohydrate, and per gram, fat releases almost three times as much energy as carbohydrate. The process by which fat produces ATP is called aerobic lipolysis. Additionally, proteins can be used to generate energy, although they normally provide only 6-7% of the body’s energy needs; this can increase to 10-15% if the body’s carbohydrate stores are completely depleted.4
Phosphates. Given the central role of phosphate as ATP in all biochemical energy systems, increasing phosphate stores in the muscles theoretically might allow the ATP system to function longer and help hasten recovery of depleted ATP stores. (See Figure 1.) Phosphate loading is one of the older ergogenic strategies, which usually involves athletes taking 1 g of various phosphate salts three or four times daily for up to a week. Three early studies found that the onset of anaerobic glycolysis was delayed by phosphate loading, but five subsequent studies found no benefit.5 Variations in the study designs and the formulations used may have led to the inconsistent results.
Currently, the research basis for phosphate loading is unclear but intriguing, given the relatively consistent results among those studies with beneficial findings. However, caution is needed before recommending long-term use of phosphate supplements. Phosphate levels are sensed by the parathyroid glands and thus are linked to serum calcium metabolism. Elevated plasma levels of phosphate lead to secretion of parathyroid hormone, which accelerates kidney excretion of phosphate.6 Calcium is reabsorbed from bone to facilitate this excretion, leading to concerns about calcium balance in athletes taking phosphate supplements.
Creatine. Creatine is one of the most popular sports supplements, especially among high school football and baseball players. Creatine forms a complex with phosphate (creatine phosphate, CP) that is required to replenish ATP stores in muscles. (See Figure 1.) Creatine is essential for short, intense, anaerobic exercise. Its role in exercise has been known since 1847 when the meat of wild foxes was shown to contain 10 times more creatine than that of sedentary foxes raised in captivity.7 Creatine burst onto the athletic scene in the 1990s when Olympic sprinters admitted they were using it as a legal ergogenic aid. Creatine is not banned by the International Olympic Committee (IOC) or the National Collegiate Athletic Association (NCAA) because it is readily available in meat and fish.
Supplemental creatine theoretically would increase CP stores, thus making more energy immediately available to muscles. Muscles containing additional stored creatine would be expected to replenish depleted CP stores faster, which might hasten an athlete’s recovery during repeated bouts of intense exercise. Creatine supplementation usually consists of a loading period of 20 g/d for four to six days (usually taken as 5 g four times a day with food). This is then followed by 2 g/d as a maintenance dose. Others claim the same tissue levels are reached after one month taking 3 g/d as a single dose.
More than 30 randomized, controlled studies have been performed on creatine, though none with more than 40 subjects. A meta-analysis of 32 studies presented at the American College of Sports Medicine 2000 meeting showed no overall effect of creatine supplementation on anaerobic performance.8 However, some patterns are visible when the studies are sub-grouped into similar categories.9 Oral creatine supplementation does not appear to improve single-bout anaerobic exercise, submaximal exercise, or aerobic exercise. Improvements here would not be expected since the ATP-CP system is not highly significant with these types of exercise.
However, some improvements generally have been seen with repeated bouts of maximal exertion lasting 6-30 seconds with a few minutes recovery. This type of exercise would be expected to be strongly dependent on CP. Many football plays, hitting and running the bases in baseball, and playing soccer depend heavily on the CP system. Four studies published in 2000 found positive effects for creatine supplementation accompanying interval training for cyclists, soccer players, and weight lifters.8 In this type of training, athletes do intense, short-duration exercises, followed by a recovery period (the interval), and then repeat the cycle. None of these studies examined if athletes’ competitive performances improved, although creatine supplementation appeared to allow them to train more vigorously. Great variability also has been noted in the responses of different athletes to the supplements.
Creatine supplementation appears to provide benefit for specific types of intense, short-duration exercise. Benefits for endurance, single-burst, and recreational exercise have not been demonstrated. Although few adverse effects have been reported, there is some concern that creatine may cause kidney problems in those already predisposed to kidney disease. One study has followed a group of athletes using creatine for up to five years.10 Nine athletes, who used between 1 and 80 g/d creatine, were compared to 85 physical education and physical therapy students who were not taking creatine supplements. No significant differences were found in plasma or urine levels of creatinine, urea, or albumen. Plasma creatine levels were not significantly different, but urinary creatine levels were almost 38 times higher, on average, among those taking the supplements. The authors concluded that creatine supplementation has no detrimental effects on the kidneys.
Anecdotally, creatine supplementation is reported to lead to muscle cramping and water retention, but these adverse effects not been confirmed in studies. In January 2001, the Food Safety Agency in France (www.afssa.fr) called for creatine to be listed as a banned substance because of its potential to cause cancer and other tissue damage, especially when taken long-term. There is no information on its impact on adolescents. The American College of Sports Medicine recommends against creatine supplementation for those under 18 years.11
Pyruvate. Pyruvate is a three-carbon molecule made when glucose is split in two by metabolism. (See Figure 2.) Pyruvate developed a reputation as a "fat burner" based on two studies by Stanko, which have not been replicated.12 Stanko used a combination of 25 g pyruvate with 75 g dihydroxyacetone (DHA), a metabolite produced immediately before pyruvate during glycolysis. Four other studies by Stanko found that obese women confined to metabolic wards lost more weight and more fat when taking pyruvate and DHA than those taking placebo. However, the applicability of these results to athletes is questionable.
The mechanism by which pyruvate might be ergogenic is unknown. Some have speculated that pyruvate may enter a "futile cycle" where a reaction proceeds forward and backward, continuously expending energy.13 This may benefit those seeking to lose weight, but not athletes. Since pyruvate is a natural substrate for aerobic and anaerobic glycolysis, theoretically it would provide calories just like other carbohydrates.
While pyruvate as an ergogenic aid is said to be research-supported, the two published studies were conducted with untrained men. Stanko himself recommends that athletes take 2 g/d pyruvate, but this differs completely from the dosage used in his trials. Commercial preparations also use a different proportion of DHA, or none at all. Between one-third and one-half of the research participants had diarrhea and borborygmus, which would be counterproductive in athletes. Long-term effects of supplementation have not been examined. Until Stanko’s results are replicated with athletes, use of pyruvate is unwarranted.
Chromium. Chromium is more popularly used in weight-loss products, but also is alleged to be an ergogenic aid. Chromium is an essential trace element involved in the normal functioning of insulin.14 The Adequate Intake Level for chromium set by the Institute of Medicine (IOM) in 2001 was 35 mcg/d for young men and 25 mcg/d for young women.15 However, little detriment has been found in those consuming 15-25 mcg/d. Such small amounts are difficult to measure accurately, which has hampered clinical research with chromium.
Chromium supplementation has been demonstrated to improve diabetes symptoms for those who also are chromium deficient. Results have been variable with diabetics having normal chromium intakes. Insulin facilitates metabolism of glucose and fatty acids, and transport of amino acids into muscle. On this basis, chromium has been touted as a fat burner and muscle builder. Four studies of athletes given 200 mcg/d of chromium showed no increase in muscle mass or decrease in body mass.14 This matches the general lack of efficacy found with studies of chromium for weight loss.16
No adverse reactions were reported in any of the clinical studies with chromium supplements, and the IOM report found insufficient evidence to set a Tolerable Upper Intake Level. Animals given large daily doses of chromium showed no adverse effects, although two in vitro tests found evidence of chromosomal damage. Some have raised concerns with the particular formulation of the mineral as chromium picolinate, which increases its absorption but also may make adverse effects more likely. A small number of case reports of adverse effects exist, while the U.S. Food and Drug Administration (FDA) has received more than 500 adverse event reports involving chromium as part of multi-ingredient herbal remedies.17 Overall, the efficacy of chromium as an ergogenic aid is questionable.
Carnitine. Turning from ergogenic aids used to impact glycolysis, carnitine is used to improve fatty acid metabolism. Carnitine is an amino acid, although different from those found in proteins. Once thought to be a vitamin, it is now regarded as non-essential because sufficient quantities are made endogenously from dietary amino acids. Fatty acids must be transported into the mitochondria of muscle cells before being metabolized to release their energy. This process requires carnitine. Theoretically, carnitine supplementation might allow athletes to utilize fatty acids better, spare glycogen stores, and thus lead to improved performances in endurance events.
Carnitine supplementation studies have failed to demonstrate regularly that oral ingestion of carnitine leads to increased muscle carnitine levels.5 Some studies have shown that fatty acid metabolism improved and glycogen stores were spared, but an equal number have demonstrated no benefit.18 Those studies that examined exercise performance demonstrated no benefits from carnitine supplementation.
Carnitine usually is recommended in doses of 2 g/d. Few side effects have been noted at this dose, although some people experience diarrhea. The long-term effects of taking carnitine have not been tested, either for safety or efficacy in endurance athletes. Carnitine is available in two isomeric forms: D-carnitine and L-carnitine. The form found in nature is L-carnitine and this is the only form that should be used. D-carnitine may interfere with endogenous synthesis of L-carnitine, leading to its deficiency, which can result in muscle weakness and dysfunction.
Coenzyme Q10. Coenzyme Q10 (also called CoQ10 or ubiquinone) is another nutrient found in mitochondria. It plays a vital role in the electron transport chain (ETC), which directly involves oxygen in the release of energy from nutrients. For this reason, CoQ10 supplementation has been recommended for endurance athletes as a way to maximize aerobic metabolism. Early reports of six studies appeared to support this finding, in addition to numerous other reports of the benefit of CoQ10 in treating heart disease.18 However, these early reports were from conference proceedings that have not been published.
More recent controlled studies published in peer-reviewed journals showed no benefits from CoQ10 supplementation in triathletes, marathoners, cyclists, and untrained men.19 CoQ10 is an antioxidant, which is why some believe it is beneficial in preventing heart disease. A recent study of CoQ10 given along with other antioxidants showed no ergogenic effect.20
No adverse effects were reported after taking 70-150 mg/d CoQ10 for several weeks. However, one study reported evidence of muscle damage after intense exercise in athletes who took 120 mg/d CoQ10 for 20 days.21 Given that there is no evidence that CoQ10 supplements are effective ergogenic aids, any risk would speak against their use by athletes.
Glutamine. Glutamine is a nonessential amino acid, although some authorities have reclassified it as "conditionally essential." This means that under certain circumstances the body is unable to make sufficient glutamine endogenously and supplementation may be required. Glutamine plasma levels are lower during catabolic conditions, such as those following surgery, trauma, sepsis, burns, and extended, high-intensity exercise.22 The body’s largest stores of glutamine are in skeletal muscle, which can be broken down to replenish plasma glutamine levels. Protein breakdown and tissue wasting also can occur because of elevated cortisol levels, which can arise as a result of prolonged physical stress.
Supplemental glutamine is thus advocated as an anticatabolic agent to counteract cortisol and replenish plasma glutamine levels. Hospital patients with major physiological stress sometimes are given glutamine supplements. Glutamine is an important energy source (along with glucose) for many cells in the immune system, including lymphocytes and macrophages. Several studies have demonstrated that athletes have higher incidences of upper respiratory tract infections (URIs) following prolonged, endurance exercise. For example, 13% of athletes who completed the Los Angeles marathon had infectious illnesses the week after the race compared to 2.2% of athletes with similar training regimens who did not compete that day.23 Runners who train more than 60 miles per week have a higher risk of infection, as do dancers and military personnel after intensive training.24
Athletes use glutamine supplementation to counteract both cortisol production and immunosuppression following exercise. Clinical studies have focused on glutamine’s effect on the immune system, with results in athletes being contradictory. The results of eight small studies were combined and showed that athletes had fewer URIs in the week following a marathon or ultra-marathon if they consumed glutamine immediately after the race.25 The incidence of URIs in athletes who drank 5 g glutamine in two portions after the race was 19.2%, compared to 51.2 % among those who drank a placebo drink.
However, a number of other studies with marathoners, swimmers, and cyclists found lower plasma glutamine levels after prolonged exercise, but unchanged immune cell counts.12 Correlations between physiological measurements and incidences of URIs were not found in the study with swimmers. Overall, there is little clinical evidence to support the use of glutamine supplements except immediately after an intense endurance event to reduce the chances of developing a URI in the following week. Glutamine is safe and not known to interact with other drugs or supplements.
HMB. Beta-hydroxy-beta-methylbutyrate (HMB) is a normal breakdown product of the essential branched-chain amino acid, leucine. HMB also occurs naturally in high levels in catfish and citrus fruits.12 Animals given HMB demonstrated less protein breakdown and a slight increase in protein synthesis. Athletes, therefore, take HMB hoping it will reduce protein wasting during periods of high stress and exercise. Two studies have shown evidence to support these claims, although overall the results remain preliminary.
Forty-one untrained men on a high-protein diet were randomly assigned to receive either 0, 1.5, or 3.0 g/d of HMB.26 After lifting weights for 90 minutes, three days a week for three weeks, the men taking HMB had 20-60% lower levels of biochemical markers that indicate protein breakdown. Muscular strength increased 8% for those in the placebo group, 13% for those taking 1.5 g HMB, and 18.4% for those taking 3.0 g HMB. In the second study, 28 athletes took either 0 or 3.0 g HMB and lifted weights for two to three hours, six days a week for seven weeks. At two, four, and six weeks, the supplemented group had a significantly greater increase in fat-free body mass than the placebo group. However, the difference between the groups peaked between weeks two and three, and was no longer statistically significant at week seven. The HMB supplemented group increased in bench press strength compared to the placebo group, but not with the squat lift or hang clean.
These results suggest that HMB may be effective as an ergogenic aid, but the second study suggests the benefits may be short-lasting. Until these studies are replicated, enthusiasm for HMB should be restrained. The safety of taking HMB for extended periods of time also must be investigated.
Steroidal Ergogenic Aids
Testosterone, the chief male hormone, has both anabolic effects that increase muscle mass and strength and androgenic effects that lead to masculinization. Synthetic steroids of interest to athletes attempt to maximize the anabolic effects while minimizing the androgenic effects. Some of the more commonly used anabolic agents include nandrolone, stanozolol, oxandrolone, and oxymetholone.6 These agents are banned by most sporting organizations, yet their use remains high in certain sports. The 1990 Anabolic Steroids Control Act made it more difficult to obtain these without prescription, but a black market thrives on the drugs, often sold for 10 times their retail cost.
Considerable debate has occurred over the years regarding whether anabolic steroids improve athletic performance and what risks they might carry. Some clinical research suggests anabolic steroids do not increase muscle mass or strength, yet many athletes anecdotally report significant gains. One reason for this discrepancy may have to do with the way steroids are used by athletes. Athletes usually combine steroid use with high-intensity training and protein-rich diets. Many different steroids are taken in complicated regimens that allegedly maximize the anabolic effects and minimize the risks of both adverse effects and getting caught. Athletes usually will give themselves 10-100 times the doses clinical researchers would recommend. On top of this, athletes often take other supplements and herbal remedies reputed to stimulate the body’s production of endogenous anabolic steroids. These differences may account for discrepancies between the reputation of anabolic agents in the gym and the medical literature. However, more recent research with higher doses of anabolic agents do demonstrate an ergogenic effect.27 Coupled with this are recent revelations concerning the systematic use of anabolic steroids in the former East Germany, especially by female athletes, which led to their dominance in many events during the 1970s and 1980s.28
Anabolic steroids have been implicated in causing serious adverse effects.6 Exogenous steroids will suppress the body’s own production of testosterone. This effect can continue for months after the anabolic agents are discontinued, and some cases of sterility have been reported. In addition, gynecomastia, prostate problems, connective tissue damage, and increased blood platelet aggregation have been reported. Anabolic agents are metabolized by the liver, leading to concerns about liver damage after long-term use. Oral anabolics in particular lower HDL cholesterol levels and elevate LDL and total cholesterol levels, which could put the athlete at higher risk for coronary heart disease. Women who take anabolic steroids are also at higher risk for virilization, masculinization, altered menstrual function, hirsutism, decreased breast size, and enlarged clitoris. Taking steroids may lead to premature closure of bone plates in adolescent boys and girls, thus disrupting their normal growth patterns.
Given the wide range of serious and life-threatening side effects, and widely accepted principles of sports ethics, most sporting organizations ban the use of anabolic agents by athletes. Yet a few physicians and pharmaceutical researchers continue to produce and prescribe agents to keep athletes one step ahead of those enforcing these bans. At the same time, some athletes turn to legal sources of steroids—prohormones. These naturally occurring compounds are sold as dietary supplements in the United States without restriction. Yet there is even less information available on their effectiveness, and just as much concern about their safety, especially in adolescents.
The use of various supplements is usually justified by their role in the synthesis of testosterone. However, Figure 3 shows that these biosynthetic pathways are interwoven and balanced in complicated ways. Adding one exogenous component to this web of steroids influences many of the others, often in unpredictable ways.
|Androgenic human steroids|
Androstenedione. The steroid androstenedione (or "andro") occurs naturally in Mexican wild yams and Scotch pine, and thus can be sold practically unregulated as a dietary supplement in the United States under the 1994 Dietary Supplement Health and Education Act (DSHEA). Humans produce andro naturally in the adrenal glands and gonads and it then can be converted into testosterone, estrone, estradiol, androsterone, and other steroids. (See Figure 3.) Androstenedione’s direct anabolic-androgenic activity is weak.
Andro was first developed as an anabolic agent in East Germany in the 1970s. It was used as a nasal spray, allegedly producing higher serum testosterone levels that were short lasting to avoid detection at competitions. It appeared on the U.S. athletic scene in 1996, and received much publicity when Mark McGuire announced he was using it during his successful bid to break Roger Maris’ home run record.29 A year later, after much controversy surrounding his example to young athletes, McGuire announced he no longer used andro.
The first controlled study on andro as an ergogenic aid was published in 1999.30 In the first part, 10 healthy men were randomly assigned to receive either 100 mg androstenedione or placebo. Those taking andro had significantly elevated blood androstenedione levels for 4.5 hours, which had dropped again within six hours of taking the dose. Other serum hormone and testosterone levels remained unchanged.
In the second part of the study, 20 healthy men were randomly assigned to androstenedione (100 mg tid for two weeks, followed by a week off to simulate the practice of "washing out" used by athletes) or placebo. The cycle was repeated three times. All subjects were supervised lifting weights for all major muscles three times weekly on nonconsecutive days. Body composition, muscle strength, and muscle fiber analysis changed for all subjects as would be expected with a weight-training program. The two groups showed no significant differences in these changes or in their blood testosterone levels. The only differences in their blood analyses were that those taking andro had significantly higher estradiol, estrone, and estrogen levels, and 12% lower HDL cholesterol levels. These changes raised concerns about the negative effects of long-term andro use in causing cancer and heart disease.
Another double-blind study randomly assigned 40 middle-aged, trained men to one of three groups.31 Each person consumed one 50 mg capsule of either placebo, androstenedione, or DHEA (dehydroepiandrosterone) bid. After 12 weeks, there were no significant differences between the three groups in lean body mass, strength, or testosterone levels. No adverse effects were reported.
Two more andro studies were published in 2000. The first involved 10 men who had lifted weights for several years and never used anabolic steroids. They were randomly assigned to take either 200 mg androstenedione or placebo for two days and then perform a heavy resistance-training program.32 Blood samples were drawn for 24 hours starting the morning of the second dose. Two weeks later the men repeated the protocol, except they ingested the other material in this double-blind, crossover study.
Blood plasma levels of androstenedione were two to three times higher than baseline after consumption of the supplement, but unchanged after the placebo. However, total testosterone and free testosterone levels were unchanged in both groups. After 90 minutes of weight lifting, total and free testosterone levels were transiently elevated in both groups, but the difference was not statistically significant. Those taking andro showed significantly elevated estradiol levels compared to placebo.
The second andro study conducted in 2000 randomly assigned 50 men to receive either placebo, androstenedione (100 mg bid), or androstenediol (100 mg bid).33 Androstenediol is closely related to androstenedione. (See Figure 3.) For 12 weeks, the subjects exercised three times a week under the supervision of a personal trainer who recorded all exercises completed. After four weeks, the androstenedione group had significantly elevated free and total testosterone levels compared to androstenediol and placebo. However, by the end of the study there were no differences. Both andro supplements led to significantly elevated levels of estradiol and estrone, which remained elevated until the end of the study. No significant differences were found between the three groups in body composition or muscle strength tests.
All controlled studies have shown similar results. Andro supplementation increases the plasma levels of androstenedione, which leads to increased production of female estrogen hormones, but not testosterone. When testosterone levels did increase, they were always short-lived. Supplementation produced no body composition or muscle strength improvements. Therefore, androstenedione appears to have none of the advantages athletes seek, and all of the dangers inherent to anabolic steroid abuse.
The four studies reported thus far have all involved men. The early German work with androstenedione involved female athletes. Also, a 1966 study with radioactive tracers found that androstenedione leads to only 0.3% of the testosterone produced in males, but to about 60% of that produced in females.32 It thus appears theoretically unlikely that men will experience any anabolic benefit from androstenedione supplements, although the effects in women have not been examined in controlled studies.
Androstenedione and androstenediol are banned by many sports organizations, including the IOC and NCAA.34,35 Consuming these products will, in most cases, lead to a positive urine test for nandrolone, another banned anabolic agent.1 The quality of andro products available in the United States also is problematic. Of nine products tested in one study, six failed the commonly accepted USP standards of containing between 90% and 110% of labeled quantities.1 One contained no androstenedione at all, and one contained 10 mg testosterone without revealing this on its label.
DHEA. DHEA is another testosterone precursor that has been used as an ergogenic aid. DHEA also is present in the blood as its sulfate ester (DHEAS) and together these constitute the most abundant steroid in humans. However, both forms have weak steroidal actions and appear to act primarily as precursors for other steroids. (See Figure 3.) Much remains unknown about DHEA’s effects in the body, although its level peaks when people are in their 20s, and then gradually decreases as a person ages. For this reason, some have claimed that DHEA supplementation is the fountain of youth and the answer to all health problems. Prior to 1994, DHEA was an unapproved drug available only by prescription, but DSHEA reclassified it as a dietary supplement. Sales immediately soared, and athletes began taking it as if it were an anabolic steroid. The IOC and NCAA banned its use.34,35
Much of the research claiming to support DHEA’s effectiveness has been conducted on animals. Of relevance to athletes, these studies have found that DHEA can increase muscle mass, reduce fat mass, improve insulin sensitivity, and even extend life span.6 However, the relevance of these studies for humans is questionable since only humans and a few primates synthesize and secrete DHEA and DHEAS.36
In human research, a few small studies have found some benefits when older men and women take DHEA supplements (usually 100 mg/d). Supplementation returned blood DHEA levels to their youthful levels, with women (but not men) also having some increase in androstenedione and testosterone levels. In one study, older men (but not older women) reported increases in knee and lumbar back strength.36
The first clinical trial of DHEA had two parts.37 In the first, 10 healthy, untrained men took 50 mg DHEA which led to significantly elevated blood androstenedione levels within 60 minutes, but testosterone and estrogen levels remained unchanged. In the second part, 19 healthy men were randomly assigned to DHEA (150 mg/d) or placebo. DHEA was taken for two weeks, followed by a week off to simulate washing out, and the cycle was repeated three times. All subjects were supervised lifting weights for all major muscles three times weekly on nonconsecutive days. The two groups showed no significant differences in serum testosterone, estrogen, or lipid levels. Both groups changed in strength and lean body mass as would be expected after a resistance-training program, with no statistical differences between the two groups. The only other clinical trial of DHEA for sports performance also examined androstenedione and was described in the andro section.31 No beneficial effects from DHEA supplementation were found.
DHEA use has adverse effects, being associated with acne, increased facial hair, loss of scalp hair, deepening of the voice, weight gain, decreased HDL cholesterol, abnormal liver tests, insulin resistance, and mild insomnia.6 The quality of commercial products available also has been found to be problematic. One study found that products contained between 0% and 150% of the labeled DHEA amount, with nine of the 16 products failing to meet standard pharmaceutical specifications of 90-110% of labeled amount.38 There is little reason to support the use of DHEA by athletes, and many reasons to discourage its use.
Human Growth Hormone. Although human growth hormone (hGH) is not a steroid, it is included in this section because athletes use it in the hope of obtaining an anabolic effect. A polypeptide secreted from the pituitary gland, hGH affects all body tissues. It stimulates growth of bone and cartilage and is especially important during childhood for normal development of body size. Children with a genetic deficiency in the hormone’s production are substantially shorter than average if not treated with hGH replacement therapy. Human growth hormone also enhances oxidation of fatty acids and reduces the breakdown of glucose and amino acids, which contribute to its reputation as an ergogenic aid.
Resistance training has been shown to increase secretion of hGH, leading to speculation that the growth of muscle mass seen with resistance training is mediated, at least in part, through hGH. Injections of hGH became popular among power athletes in the early 1990s. This became so prevalent that some dubbed the 1996 Olympic Games in Atlanta "the Growth Hormone Games."
Most of the data on injected hGH supplements are based on studies conducted in men 60 years or older. These men showed improvements in muscle tone, increased lean body mass, and reduced fat mass.39 However, in younger trained or untrained adults undergoing resistance training, well- controlled clinical trials showed that hGH supplementation did not increase muscle synthesis, muscle size, or muscle strength.18 There are significant concerns about hGH injections for those who are not deficient in the hormone. Insulin resistance has developed, along with fluid retention, gynecomastia, and headaches.39
Because of these concerns, hGH preparations are now available for oral administration, especially as a sublingual spray. There is no evidence that oral hGH has any effect on the body. Another recommendation has been to supplement the diet with arginine, ornithine, and lysine—amino acids believed to stimulate the secretion of hGH. A 1989 study found beneficial changes in fat and muscle mass after five weeks of supplementation with these amino acids, but later, better-designed studies have failed to replicate these findings.18 Moderate doses of these amino acids appear to be safe, but excessive intake can lead to gastrointestinal problems. Long-term, high-level supplementation may precipitate kidney or liver problems in susceptible individuals.
Herbal Ergogenic Aids
Ginseng. One of the most popular herbal remedies sold in the United States, ginseng has a reputation as an adaptogen: a substance that helps the body adapt to stressful situations.40 Given the stress of training and competition, ginseng’s popularity has extended into sports circles. In fact, ginseng is one of the few herbal remedies that has been investigated extensively by sports medicine researchers.
Ginseng demonstrates the problems inherent with the use of any herbal remedy in the United States today. The term ginseng applies to many different plant species. The ginseng used for centuries as part of traditional Chinese medicine (TCM) is Asian ginseng, or Panax ginseng. American ginseng is a closely related plant (Panax quinquefolius), but Siberian ginseng (Eleutherococcus senticosus) is only distantly related to either. Several other species have been used and sold as ginseng, but the available research for sports performance has focused primarily on Asian and Siberian ginseng.
The active ingredients in Asian and American ginseng are believed to be a group of at least 30 steroidal glycosides called ginsenosides. However, particular batches of each species contain different mixtures and amounts of ginsenosides, which may account for the different results found in clinical trials. Siberian ginseng contains no ginsenosides, but a different group of steroidal glycosides called eleutherocides. Traditionally, Asian ginseng is harvested after at least five years of growth, at which time the roots typically contain 1-2% ginsenosides.40 TCM practitioners generally recommend 3-9 g/d ginseng, usually combined with other herbs. With the availability of standardized preparations, 200 mg/d ginsenosides is the usual recommendation.
However, the plant material can vary greatly. The levels of ginsenosides vary according to species, season harvested, age of the plant, soil, and part of the root used; in 20 American ginseng plants harvested from a 1 m2 area, the ginsenoside content varied more than twofold.41 Not only does the ginsenoside content of species and plants vary, but the plant material can be processed in very different ways. The most common form is "white ginseng," which is the bleached and dried root material. "Red ginseng" is steam-cured prior to drying, which leaves a reddish color in the product. Other teas, extracts, and tinctures (alcohol-based extracts) also are available. All of these options have led to great variability in ginseng products available to athletes today.
Clinical trials on ginseng for sports performance date to the early 1970s. However, the quality of the early studies often was poor; several of them were not controlled in any way. A 1994 review of this research concluded, "there is an absence of compelling research evidence demonstrating the ability of ginseng to consistently enhance physical performance in humans."42 However, animal studies have found that ginseng and ginsenosides consistently help animals adapt to physical and chemical stress. Those studies have tended to use much higher doses (up to 100 times higher) than those given to humans.
When these same reviewers updated their analysis in 2000, they found more than 35 new reports on ginseng related to physical performance.43 While the methodological quality of these trials had improved, many still had significant problems, especially with sample size. In studies measuring physiological parameters, the largest sample size was 43, and all but three studies had fewer than 20 subjects. The doses, species, and preparations of ginseng given to athletes also varied significantly, as did the lengths of the studies.
Eight controlled clinical trials of Asian ginseng for physical performance in humans were published during the 1990s.40,43,44 Of these, six produced nonsignificant results in a variety of physiological measurements. One crossover study found no benefit during the first period of supplementation, but in the second period found that athletes lost physical fitness slower when taking 400 mg/d ginseng.45 The authors cautioned that this could have been a carryover effect from the first period. The second study with beneficial effects found improved measures of fitness in those who took ginseng and did not exercise compared to those who took a placebo without exercising.46 Ginseng provided no benefit to those who exercised. One controlled study used American ginseng and found no significant improvements. Since 1990, two controlled trials have used Siberian ginseng, with both having nonsignificant results. Overall, nonsignificant results predominate in the later, better-designed studies of ginseng for athletic performance.
Adverse effects of ginseng have been reported occasionally, although most have been relatively minor and short-lasting.44 A "ginseng-abuse syndrome" also has been alleged when people consume 3 g/d ginseng, and especially with 15 g/d. The symptoms of the latter are hypertension, nervousness, sleeplessness, and diarrhea.44 The quality of products available in the United States also has been of concern. In one analysis, only nine of 22 ginseng products passed a quality control test, with eight products found to contain higher than allowed pesticide levels.47 Although ginseng is not banned by the IOC or NCAA, one athlete at the 1988 Seoul Olympics tested positive for the banned substance ephedrine, which was traced to contamination of a ginseng product.48 This is alleged to be a consistent problem with ginseng supplements.
In spite of a relatively large number of clinical trials, ginseng has not produced the dramatic improvements commonly heard in anecdotal reports. While it is possible that the research protocols have not matched the way ginseng is used by athletes, studies consistently find ginseng has little direct impact on athletic performance. However, there is growing evidence that ginseng may offer psychological benefits that could be relevant for athletes, especially if the athletes feel more confident before competition.49 Further study is needed in this area, but it may explain the large discrepancies between research findings and the long tradition of ginseng usage. Overall, there is little research support for the use of ginseng as an ergogenic aid.
Ephedra. Ephedra also is known by its Chinese name of ma huang, as "herbal ecstasy" for its stimulant effect, and as "herbal fen-phen" for its alleged weight-loss properties. The plant material traditionally used is the rhizome and roots of Chinese ephedra (Ephedra sinica). The herb has a long tradition of use in China for several respiratory problems. The active ingredients are a group of compounds called ephedrine alkaloids. The best known of these is ephedrine, the widely used decongestant and asthma remedy. The genus Ephedra contains more than 40 different plant species, each with its own specific alkaloid mixture. Ephedra nevadensis, often called American ephedra or Mormon tea, is native to North America, but contains no ephedrine alkaloids.
The total alkaloid content of Chinese ephedra ranges from 0.4 to 25 mg/g of plant material.50 This variability has extended into the commercial products available as dietary supplements. Several hundred adverse event reports, including about 50 fatalities, have been reported to the FDA after people took ephedra products. For this reason, the FDA requires that ephedra product labels state that no more than 8 mg ephedrine alkaloids should be taken every six hours for a total of no more than 24 mg/d and that treatment should be stopped after seven days.12 However, one study found between 0.3 and 55.6 mg ephedrine alkaloids per gram of ephedra product.51 Another study found a 19-fold difference in the amounts of ephedrine alkaloids in 10 commercial products.50 These studies also found that some products contained ephedrine without any other ephedrine alkaloids. Since no Ephedra species produces only ephedrine, the most reasonable interpretation of these results is that the products were spiked with synthetic ephedrine. The variability among products could lead to people taking vastly different quantities of ephedrine, especially if they change from one brand to another.
All ephedrine alkaloids work in similar ways to epinephrine (adrenaline) as sympathomimetic agents. They stimulate numerous systems in the body, leading to faster heart rate, increased blood pressure, flushing, deeper breathing, and nervousness.52 For this reason, ephedrine and related products are banned by most sporting organizations, including the IOC and the NCAA.34,35 Ephedrine alkaloids can cause insomnia, which can be both a desired effect or an unwanted side effect. The cardiac and neurological adverse effects are more serious.
In spite of ephedrine’s stimulant effects, there is little evidence it promotes athletic performance. Five controlled clinical trials giving athletes up to 120 mg ephedrine alkaloids found no significant performance enhancement effects.40 However, combination of ephedrine (1 mg/kg) with caffeine (5 mg/kg) significantly increased time to exhaustion compared to either drug alone or placebo.53 Combined ephedrine-caffeine products also are alleged to promote weight loss, though there is little evidence to support this practice. The combination allegedly causes fat loss preferentially while increasing muscle mass.
Overall, the evidence for athletes using ephedrine alkaloids clearly points to the dangers far outweighing any benefits. Athletes should be discouraged from taking any ephedra or ma huang product. Part of the concern here arises from the poor quality of ephedra products found in several studies. In addition, ephedrine is banned by many sporting organizations, and ephedra herbal products will lead to positive drug tests.40
Caffeine. Caffeine is a unique compound in the sports world in that it is part of the diet of most athletes, has no nutritional value, and is banned by the IOC only if its level exceeds 12 mcg/mL of urine.54 The maximum urinary level allowed by the NCAA is 15 mcg/mL.35 While caffeine commonly is found in coffee, tea, cocoa, chocolate, and many soft drinks, herbal sources include kola nut, guarana paste, and maté leaves. These frequently are added to combination herbal remedies for their caffeine content. However, most of the studies have been conducted with synthetic caffeine that allows precise and reproducible dosing. Herbal caffeine sources have all the variability problems discussed of ginseng and ephedra products.
Since 1990, research has found consistent evidence that caffeine supplementation does have an ergogenic effect. Caffeine may stimulate the sympathetic nervous system and thus augment the effects of ephedrine.5 Other metabolic studies suggest caffeine may lead to the release of free fatty acids and enhance their oxidation. This could lead to a glycogen sparing effect, which might improve endurance performance.
Several controlled studies have found that both well-trained and recreational athletes improved their endurance performances by 20-50% after ingesting around 300 mg caffeine.54 These improvements increased with increasing doses of caffeine. In one study, caffeine (3, 5, and 6 mg/kg) produced ergogenic effects without side effects and without exceeding the IOC urinary output limit.55 Higher doses (9-13 mg/kg) produced greater ergogenic effects, but prevalent side effects (dizziness, headache, insomnia, and GI disturbances), and with several athletes exceeding the IOC urinary limit.
Results with caffeine supplementation prior to sprinting or intense exercise lasting less than 20 minutes have been contradictory. Ergogenic effects in these studies have been explained on the basis of caffeine’s central stimulant effects, which are believed to increase athletes’ alertness and improve mood.54 Researchers do not have a clear understanding of all the mechanisms by which caffeine affects performance.
Caffeine remains a controversial, though tolerated, ergogenic aid. Research demonstrates that it can improve endurance performance, although individual responses vary considerably. Caffeine raises ethical questions concerning how "natural" an athlete’s performance should be. Endurance athletes who consume six 8-oz cups of coffee in the hour prior to exercise will approach the IOC limit of 12 mcg/mL urinary caffeine. Capsules, tablets, and suppositories regularly are used by athletes seeking the ergogenic effects. A study of 11- to 18-year-olds in Canada found that 26% of the athletes used caffeine to enhance performance.5 Athletes taking more than 9 mg/kg sometimes reported poorer performance because of caffeine’s side effects. Some have expressed concern that caffeine’s diuretic effects may lead to dehydration, but this has not been found in research studies.54
Cordyceps. Cordyceps is another example of an ancient Chinese herbal remedy gaining a reputation as an ergogenic aid. The remedy comes from the fungus Cordyceps sinensis, which grows in the Himalayan mountains. Previously unknown female Chinese distance runners and swimmers came to international prominence in the mid-1990s and attributed their success to rigorous training and a special diet including cordyceps.56
Cordyceps extracts contain numerous compounds, many of which could contribute to an ergogenic effect.57,58 They contain relatively large amounts of adenosine, which is a vital constituent of ATP, the high-energy molecule fueling many cellular processes. (See Figure 1.) Cordyceps extracts are plentiful in the essential amino acid, tryptophan (24 mg/g), which can have a calming effect on humans and thus could contribute to improved performances. A number of tissue studies have shown that cordyceps extracts cause bronchodilation, which validates its traditional Chinese use.59 However, no clinical trials have examined the alleged ergogenic effects of cordyceps.
Harvested cordyceps is extremely expensive, but fermentation technology has made it more available to athletes and researchers. Research is starting to support the theoretical basis of an ergogenic effect, but this has not been examined in human trials. One commercial product, CordyMax, contains 525 mg of a dried extract standardized to contain at least 0.14% adenosine. The manufacturer recommends taking two capsules, two or three times daily. However, reports of contamination of imported Chinese remedies regularly occur, and cordyceps is no exception. Two cases of lead poisoning were reported in Taiwan after people ingested cordyceps powder, later found to contain 20,000 ppm lead.60
Plant steroids. Wild yam (or Mexican yams, Dioscorea villosa) is the most popular herbal remedy known to contain plant steroids. Others include saw palmetto (Serenoa repens), wild oats (Avena sativa), potency wood (Ptychopetalum olacoides), smilax (Smilax officinalis), suma (Pfaffia paniculata), and sarsaparilla (Smilax species).40 Rice bran oil also has been used as a source of gamma-oryzanol. All are used as "legal" sources of testosterone or prohormones.
However, in spite of the popularity of this approach to getting a "testosterone boost," there is no evidence that it works. One double-blind, randomized clinical trial with 20 young men examined a herbal remedy containing six prohormones, including 300 mg androstenedione, 150 mg DHEA, and 540 mg saw palmetto.61 Subjects took the supplement for two weeks and then took a week off, and repeated the protocol three times. They lifted weights three days a week for eight weeks. At the end, the supplemented group did not differ from the placebo group in testosterone levels or muscle mass or strength gains. However, the supplemented group had significantly higher levels of estrogens, once again raising concerns about the effects of these supplements long-term.
Taking plant steroids has a significant problem in its theoretical basis. Manufacturers of DHEA and other steroids use a complicated series of chemical reactions to convert plant steroids into steroids found in the human body. There is significant evidence that the human body cannot do these reactions and therefore cannot convert plant steroids into human steroids.62 In addition, plant steroids are poorly absorbed from the human intestinal tract and may elicit hormonal changes that actually reduce endogenous testosterone production.63
Powerful pressures exist in the sports world today. The rewards for successful performance are increasing. Athletes are under greater and greater pressures, at younger and younger ages, to maximize their performances. Little wonder they are turning to chemical methods to enhance their natural endowment and their hours of training and practice. However, sporting bodies like the IOC and NCAA have banned those ergogenic aids that actually work.34,35 Athletes who do not abide by the ethical standards of fair competition will find themselves barred from competition if they fail blood tests.
Some athletes turn to natural supplements in the hope of legally obtaining ergogenic aids. If these substances contain anabolic agents, they will still fail the blood doping tests. However, the danger with dietary supplements often goes beyond the mere fact that the substances are ineffective and carry significant risks of adverse effects. The quality of many of these products also is questionable. Although the pressure to try ergogenic aids is understandable, the ethics of good sportsmanship insist on limiting performance enhancement to making the most of one’s natural gifts, hard work, and proper nutrition. While some question whether these are old ethics for a time gone by, they help protect the health of those who most exemplify the amazing capabilities of the human body. How ironic it is that in trying to get the most out of their bodies, some appear unconcerned about the effects of what they put into their bodies. Physicians should do their best to help promote the health of athletes by giving them reliable information about the ergogenic aids available as dietary supplements. v
Dr. O’Mathúna is Professor of Bioethics and Chemistry at Mount Carmel College of Nursing in Columbus, OH.
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