Popular Ergogenic Drugs and Supplements in Young Athletes

Physiology

Anabolic steroids are synthetic derivatives of the hormone testosterone. The chemical structure has been modified by manufacturers to maximize anabolic effects by delaying metabolism via alkylation of the 17-α position or carboxylation of 19-β hydroxyl group on the sterol D ring.²⁰ Steroids bind to androgen receptors within the cell cytoplasm. They then are transported into the nucleus before binding DNA and increasing mRNA transcription, which enhances contractile and structural protein synthesis.^9,21

Steroids have 3 general effects that benefit the athlete. Binding androgen receptors promotes a positive nitrogen balance in muscle, which produces an anabolic state.²² However, in the normal physiologic male individual, endogenous testosterone nearly saturates the available androgen receptors, making this effect of questionable importance. Therefore, it becomes critical that steroids are also anticatabolic. In the overtrained individual, glucocorticoids are increasingly released, which promote the breakdown of muscle glycogen for energy.²³ Once available androgen receptors are saturated, exogenous steroids competitively inhibit the binding of catabolic glucocorticoids, thereby preserving muscle mass being gained.²⁴ Finally, anabolic steroids have significant emotional effects. This is often manifest in increased aggression, which can push athletes to train more intensely, more often, or longer.²⁵

Dosing

Oral, injectable, and newer transdermal steroid preparations are available. Oral forms are short-acting and eliminated over days, whereas injectable steroids have longer lasting effects but risk positive drug testing up to months after use.⁴ Steroids are usually used in the off-season, when athletes are strength training and when use is least likely to be detected. Steroids are generally taken in 4- to 12-week cycles. Athletes often “stack” multiple steroids at the same time and “pyramid” the dosing schedule, taking highest amounts in the middle of cycles. Although attempting to maximize results, athletes may consume doses 50 to 100 times the amount that would replace physiologic steroid levels.⁹ Between dosing cycles, it is typical for users to have a period of abstinence, known as a “drug holiday,” of varying duration. The most recent so-called “designer steroids” are steroids that are made with simple chemical modifications to preserve anabolic activity while being undetected during drug testing.²⁰ Common steroid preparations are listed in Table 2.

Effects

Although not every study agrees, the consensus today is that these drugs do increase athletic measures with objective gains in strength and fat-free mass.^26–28 This fact was conceded in the 1980s by the American College of Sports Medicine.²⁹ Haupt and Rovere²³ reviewed the literature in the 1980s and concluded that athletes could not expect aerobic gains but that strength gains were substantial. Effects were most evident in those with previous weight-training experience and when single repetition maximal efforts were measured. A recent double-blinded study over a 12-week training cycle confirmed significant gains over placebo in ultrasound-measured muscle pennation and overall strength on a bench press test.³⁰ These drugs increase isokinetic and isometric strength, as well as muscle mass both via muscle hypertrophy and the formation of new muscle fibers.³¹ It is important to note that because of ethical concerns, these studies on the effects of anabolic-androgenic steroids as well as those subsequently discussed concerning other ergogenic drugs were performed on adults, although they offer our best controlled evidence and are presumed to represent effects equally in adolescents.

Adverse Effects

Nearly 30% of steroid users experience mild subjective adverse effects.²³ Steroid supplementation has potential adverse effects in multiple organ systems. From an endocrine perspective, exogenous steroids provide feedback inhibition of luteinizing and follicle-stimulating hormones, which produces testicular atrophy and possible infertility. The additional steroids also undergo peripheral aromatization to estrogens, which can lead to irreversible male gynecomastia. It is also common to see premature balding, acne, and precocious puberty.²² Steroids have an impact on the cardiovascular system by adversely affecting lipid profiles, raising blood pressure, and causing left ventricular hypertrophy.^32–34 The oral preparations pose the greatest risk to the hepatic system, with common transient disturbances including cholestasis and nonspecific increases in liver enzymes. There are also rare cases of peliosis hepatitis with blood-filled liver cysts and anecdotal reports of hepatocellular carcinoma with proposed links to steroid abuse.³⁵ The musculoskeletal system, although with grossly increased strength, exhibits dysplastic collagen fibrils that can predispose to muscle strains and ligament sprains.³⁶ The immature athlete after initial acceleration of bony growth may have premature physeal closure, permanently shortening their final adult height.³⁶ Infections such as HIV, hepatitis B, and hepatitis C remain a concern associated with injectable preparations as several studies confirm that between 25% and 33% of adolescents who are taking steroids share needles.^37,38 Specific to female users are adverse effects such as deepened voice, clitoromegaly, and loss of breast tissue, with elements of this virilization being irreversible.²² Psychologically, steroid users may experience severe mood swings from depression to mania and aggression that cannot be channeled properly outside the athletic arena. Using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, the American Psychiatric Association's standard for defining mental illnesses, it has been reported that nearly 50% of steroid users in a series met criteria for being dependent on or abusing steroids (Table 3).³⁹

Apart from medical adverse effects, several investigators have documented social risks to steroid use. Middleman et al⁴⁰ documented an association with other high-risk activities such as driving under the influence, carrying weapons, and engaging in unsafe sexual practices by young users. Durant et al⁴¹ also elaborated on the increased use of other illicit substances by youths who take steroids, including marijuana and alcohol.

Legal/Sports Aspects

The Anti-Drug Abuse Act in 1988 first prohibited the distribution of steroids for any purpose other than treatment of a disease. This was followed by the Anabolic Steroid Control Act of 1990, which placed steroids under Schedule III of controlled substances. The illegal possession of anabolic steroids is punishable by 1 year in prison and/or a minimum $1000 fine, with selling or intent to sell incurring a 5-year prison sentence and/or a $250000 fine. Steroids are banned from use by all major sporting leagues, although each governing body has individualized testing and penalization policies.

Incidence

Estimates of high school steroid use range from 4% to 11% in boys and up to 3.3% of girls.^1,25 The landmark study in this area was performed by Buckley et al.² This nationwide survey of >3000 boys found that 6.6% of male high school seniors had tried steroids, with 67% beginning use by 16 years of age and 40% using multiple cycles. This was later confirmed in a survey of Indiana high school football players documenting a 6% use rate (mean age at first use: 14 years) and a 2003 nationwide Centers for Disease Control and Prevention data finding a 6.4% use of steroids by 12th-grade boys.^1,42 Subsequent publications have continued to document childhood steroid use with consistent findings of 2% to 3% of students using steroids in ages from 9 years to young teens, with numbers reaching 9% among middle school children who reported being gymnasts or weightlifters.^38,43,44 Unfortunately, even when examining only ninth-graders, one investigator found percentages that quickly reflected previous estimates for use over the entire high school population with 5.3% of boys and 1.5% of girls using steroids in a survey of nearly 2000 Georgia students.⁴⁵ The ongoing Monitoring the Future study, which has the largest nationwide cohort of nearly 50000 students, showed a 1.3%, 2.3%, and 3.3% annual prevalence of male steroid users in the 8th, 10th, and 12th grades, respectively, in 2004. Girls in the 12th grade had a 1.7% use rate of steroids in the past year, whereas the Centers for Disease Control and Prevention found a 3.3% lifetime prevalence of steroid use in 12th-grade girls.^1,46 Although the numbers from the Monitoring the Future survey are more modest than other reports, it is important to remember that these numbers reflect the entire student population, not just athletes, and that a concerning trend was found with 12th-graders showing a steadily decreasing perceived risk of steroid use yearly since 1993, with now only 55% of seniors viewing occasional steroid use as a great risk.⁴⁶ Even in Buckley's initial work, it remains noteworthy to realize that nearly one third of young steroid users do not participate in formal school sports.²

In the 1980s, estimates of steroid use reached 20% for division I college athletes.⁴⁷ Subsequently, the National Collegiate Athletic Association (NCAA) began surveying its athletes to better define the demographics of substance use in this population. The latest NCAA survey in 2001 polled >21000 student athletes in all championship sports and all divisions.⁴⁸ They reported that 1.4% of these individuals used steroids in the past 12 months. Recent independent studies of college athletes, however, raise the possibility of underreporting to the NCAA as results show up to 9% of athletes using steroids on 1 campus.⁴⁹ Worrisome trends discovered by the NCAA included a change in utilization, with most athletes in 1997 using steroids to recover from injury, whereas current athletes mainly reported use to improve performance or appearance. Also, steroids were the only ergogenic drug class to increase in all collegiate divisions. Furthermore, steroid use was beginning earlier than in the past, with 42% of users reporting first use in high school and 15% beginning steroids in junior high or before.⁴⁸

Physiology

Androstenedione and closely related dehydroepiandrosterone (DHEA) are 2 popular steroid precursors, or prohormones. DHEA is a weak androgen that is produced in the adrenal cortex, whereas androstenedione, a more potent anabolic-androgenic steroid, is made in the adrenal glands and gonads. DHEA is converted in the body to androstenedione, which then can be transformed into either testosterone or estrone (Fig 1). ⁵⁰ Athletes use these substances with the belief that they will boost testosterone levels, thereby having ergogenic effects similar to anabolic steroids.

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FIGURE 1

Steroid pathway for DHEA and androstenedione showing conversion to testosterone or estrone. Adapted with permission from DPC Company Web site. Available at: www.dpcweb.com/documents/news%26views/fall_2003/images/androsteine.html.

Dosing

DHEA's recommended dosing is in a range of 50 to 100 mg/day for up to 1 year. The number of adverse effects increases at doses that exceed this amount, although athletes may well take more than the recommended amounts.^51,52 Although now off the supplement market, androstenedione's upper limit for dosing was 100 to 300 mg/day.

Effects

In 1962, Mahesh and Greenblatt⁵³ published that androstenedione given to 2 female individuals resulted in increased testosterone levels. Since that time, there has been little support for these precursors having any ergogenic effects, although their popularity soared after Mark McGwire admitted to using androstenedione during his 1998 quest to break Roger Maris's single-season home run record. Leder et al⁵⁴ in 2000 reported that men who were given androstenedione showed increased testosterone levels, although this effect was seen only in the first few hours after initial use. Furthermore, the early boost in testosterone levels reached only the upper limit of normal for physiologic male individuals. Later, after several weeks of use, the only hormone change was increased estrogen.⁵⁴ Most studies have found no change in testosterone levels but have confirmed increasing estrogen levels in male individuals.⁴ Specific to athletes, King et al⁵⁵ in 1999 published a series of 20 healthy male individuals with 8 weeks of standardized resistance training, whereby androstenedione was given in a double-blinded manner versus placebo. At the conclusion of the testing period, those who received the drug showed no change in any athletic measure or testosterone levels but were found to have significantly increased estrone and estradiol levels. In the literature to date, there is no convincing evidence that these prohormones have any true benefit for the athletes, and as Tokish et al²⁰ reported in 2004, “The marketing of this supplement's effectiveness far exceeds its science.”

Adverse Effects

Although androstenedione and DHEA are without proven benefit, they are not without risk. As they share a metabolic pathway with anabolic steroids, they share several common adverse effects. These include adverse changes in lipid profiles as well as potential male gynecomastia and virilization of female individuals. Use of these substances may also downregulate endogenous testosterone over time.⁵⁶ In addition, priapism has been reported and animal studies have found resultant hyperplastic prostatic changes with use.^57,58 Finally, although DHEA is a legal supplement, impurities during production can place athletes at risk for testing positive for a banned substance.

Legal/Sports Aspects

In 2004, a new Steroid Control Act that placed androstenedione under Schedule III of controlled substances effective January 2005 was signed. DHEA was not included in this act and remains an over-the-counter nutritional supplement. Androstenedione now is banned by all major sporting leagues, including Olympic and collegiate sports.

Incidence

Sparse literature is available for evaluating use of androstenedione and DHEA. In 2002, Reeder et al⁵⁹ surveyed 475 high school students and found that 4% of this population of athletes and nonathletes used steroid precursors within the past year. Meanwhile, the NCAA's 2001 study found that 5.3% of their athletes admitted to use of androstenedione or DHEA in the past year.⁴⁸ The high number of adolescent users in Reeder's student body cohort suggests that these drugs are being used by adolescents and again raise concern that collegiate student athletes may be reluctant to report use to the NCAA.

Physiology

Growth hormone is a polypeptide secreted by the somatotrope cells in the anterior pituitary. Secretion is pulsatile and gradually decreases after peaking during early adolescence. Growth hormone is converted in the liver into insulin-like growth factor 1, which has several effects throughout the body. Insulin-like growth factor 1 serves to increase protein synthesis, lipid catabolism, and bone growth.⁶⁰

Dosing

Growth hormone first was used in children who were growth hormone deficient. This was initially derived from cadavers and proved dangerous with the transmission of prion disease. Now, there is a biosynthetic growth hormone available. Growth hormone is produced only in injectable form. It may be used several times per month, and the cost of a 1-month supply can approach $5000.⁶¹ Athletes who take growth hormone often combine use with anabolic steroids.⁵

Effects

Although growth hormone has many benefits for those who are congenitally deficient, it does not seem to hold similar promise for healthy young athletes. No conclusive evidence exists that growth hormone enhances athletic performance.^62–64 In fact, patients who have acromegaly with an excess of growth hormone may be the most accurate model for the athlete who is supplementing an already normal hormone level. Patients with acromegaly often have weaker muscles as a result of a growth hormone–induced myopathy and have demonstrated greater exercise tolerance after treatment to reduce growth hormone levels.^65,66 Even without proven performance benefit, this drug does have several effects that attract athletes. One is that growth hormone causes perceptible fluid shifts within bodily tissues with early use, causing individuals to feel that the drug is “doing something.” Second, growth hormone has a repartitioning effect, which decreases subcutaneous fat, making it attractive to individuals who are aiming for a more toned appearance.⁶⁷

Adverse Effects

The initial use of growth hormone from cadavers risked transmission of prion diseases, but this has been resolved with the advent of synthetic growth hormone. However, injecting the synthetic form still carries with it the widely known risks of hepatitis and HIV transmission with the use of nonsterile needles. Additional risks include premature physeal closure, jaw enlargement, hypertension, and slipped capital femoral epiphysis.⁵¹ Rare but severe risks also include reported papilledema with intracranial hypertension.⁹

Legal/Sports Aspects

Growth hormone is a banned by all major sporting leagues. However, no reliable test to detect use by athletes has been developed.

Incidence

Questioning younger athletes, Rickert et al⁵ surveyed 224 boys who were in the 10th grade to assess high school growth hormone use. Nearly 5% reported using growth hormone, with 10 students indicating explicitly that it was for improving sports performance. More than half used growth hormone in conjunction with steroids, and 70% reported use more than once per month. Of concern was the fact that half of the students could not name a single risk associated with taking growth hormone.⁵ The latest NCAA study found that 3.5% of athletes reported using growth hormone in the past 12 months.⁴⁸ It is interesting that this statistic was available in the raw data but was without mention in any published conclusions.

Physiology

Creatine is formed from glycine, arginine, and methionine and is naturally produced by the liver, kidneys, and pancreas. After production, creatine is transported to muscle, heart, and brain, with 95% of bodily stores remaining in muscle. Creatine is also naturally present in the diet, mainly in meat and fish. The daily requirement of creatine is 2 g, with this amount provided half from endogenous production and half from normal diet.⁷⁴ Muscle creatine stores are in a balanced equilibrium with creatine and phosphocreatine interconverted via creatine kinase. Phosphocreatine provides energy to the muscle via its dephosphorylation, which donates a phosphate to adenosine diphosphate producing adenosine triphosphate (Fig 2). Aerobic recovery time then allows for the restoration of phosphocreatine.⁹ Phosphocreatine availability is considered the limiting factor in short, high-intensity activities, as it provides muscle with the major energy source over the first 10 seconds of anaerobic activity after free adenosine triphosphate is consumed in the first 1 second of action (Fig 3). ^75,76

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FIGURE 2

Interconversion of phosphocreatine and creatine producing adenosine triphosphate. Adapted with permission from Dr M. Jenkins, SportsMed Web. Available at: www.rice.edu/∼jenky/images/creatine.html.

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FIGURE 3

Time-dependent, dominant energy source for muscle activity. Adapted with permission from Dr M Jenkins, SportsMed Web. Available at: www.rice.edu/∼jenky/images/creatine.html.

Investigations into the tissue level effects of oral creatine seem to show several changes. Supplementation can cause an ∼20% increase in muscle phosphocreatine stores, quicken the replenishment of phosphocreatine during recovery, and buffer lactic acid as hydrogen ions are consumed during the dephosphorylation of phosphocreatine, which potentially delays fatigue onset (Fig 2).^77–79

Dosing

Creatine is recommended to be taken first in a loading phase, with athletes consuming 5 g 4 times per day for the first 4 to 6 days. The standard dosing then is 2 g/day for the next 3 months. Creatine taken in excess of this amount seems to be excreted via the kidneys.⁸⁰ A month of abstinence is standard practice after each use cycle. The Physician's Desk Reference notes that athletes should consume 6 to 8 glasses of water per day while taking creatine to prevent dehydration.⁸¹ Absorption of oral creatine does vary with diet. Carbohydrate-rich fluids tend to increase creatine absorption, whereas caffeine impairs its uptake.^82,83

Effects

Creatine supplementation does appear to have athletic benefits. However, nearly 30% of athletes do not see benefits with creatine use, thereby falling into a category of “nonresponders” who are theorized to have already maximal phosphocreatine stores.⁹ Most common, performance effects are seen in increasing strength and outcomes in short-duration, anaerobic events. Studies do not show improved endurance performance as expected given that prolonged muscle activity depends on aerobic glycolysis.⁸⁴ In a well-controlled setting, Volek et al⁸⁵ performed a double-blinded study that examined 12 weeks of creatine use including standard loading and maintenance phases in recreational weightlifters. In those athletes who were taking creatine, significant increases in fat-free body mass; bench press maximal lift; peak power production in sets of repeated jump squats; and biopsied type I, IIA, and IIAB muscle fibers were demonstrated.

Adverse Effects

Athletes who take creatine commonly experience early weight gain of 1.6 to 2.4 kg, which can be detrimental in purely speed-based events. It is also common for athletes to report minor gastrointestinal discomfort and muscle cramps, although these generally do not curb use.⁴ There have been 2 case reports of renal function compromise. One was an athlete who had previously diagnosed focal segmental glomerulosclerosis and experienced a transient 50% loss of glomerular filtration rate, and 1 previously healthy athlete reported transient interstitial nephritis.^86,87 However, at least 1 study of self-reported use over several years did not show adverse renal effects.⁸⁸ Three highly publicized deaths have occurred in college wrestlers who were known to take creatine, although official autopsy results indicated that dehydration and weight loss were at fault, not creatine.⁸¹ Additional questions remain, as there are no data to judge the effects of supplementation on the other tissues that store creatine (heart and brain), the effects of chronic use, or the effects of creatine use in minors.

Legal/Sports Aspects

Creatine remains a legal nutritional supplement today. Despite at least 1 brand's name, Teen Advantage, the American College of Sports Medicine has recommended explicitly that it is not to be used by anyone who is younger than 18 years.⁷⁹ Collegiate teams, including trainers and coaches, are prohibited from supplying creatine or other supplements directly to their student athletes.

Incidence

Questioning younger populations, 1 study found 8.2% of 14- to 18-year-olds using the supplement, with 75% of those users either unaware of how much creatine they consumed or taking more than the recommended amounts.⁸⁹ Meanwhile, looking at 10- to 18-year-olds, Metzl et al⁹⁰ reported that 5.6% of that age group used creatine, with every grade from 6 to 12 involved. It was also noted that 12th-graders used creatine much like their collegiate counterparts, with that grade reporting 44% use. Current estimates of collegiate creatine use vary from 25% to 78% of athletes.^48,91

Physiology

Ephedrine is a stimulant with a chemical structure closely related to amphetamine (Fig 4). It is derived from ephedra herbs also known as ma huang. It possesses α and β adrenergic agonistic effects, enhances the release of norepinephrine, and stimulates the central nervous system.⁹² Pseudoephedrine is closely related and also possesses central nervous system stimulant properties in addition to being a popular decongestant.⁹³

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FIGURE 4

Chemical structure of ephedrine.

Dosing

Previously available ephedrine compounds included such brands as Metabolife356 and Ripped Fuel. Before being banned in 2004, the FDA recommended that daily ephedra alkaloid intake remain under 25 mg and not be continued longer than 1 week.⁹⁴ Pseudoephedrine in cold remedies is taken in maximal amount at 60 mg. Combining ephedrine with caffeine or its herbal form guarana poses significant risk and was prohibited by the FDA in the 1980s.⁹⁵

Effects

Ephedrine traditionally has been used by athletes to provide quick energy and to aid in fat loss, consequently improving speed and appearance. The majority of studies that are available show no change in athletic performance with ephedrine use. A few investigations have reported improvements in quadriceps strength or stationary cycling, but these have involved high doses of ephedra compounds and sometimes were combined with caffeine, which poses significant risk to the athlete.^96,97

Adverse Effects

Bent et al⁹⁸ reported that ephedra accounted for 0.82% of herbal product sales but was implicated in 64% of adverse herbal reactions in the United States in 2001. Adverse reactions are wide ranging and include hypertension, arrhythmias, anxiety, tremors, insomnia, seizures, paranoid psychoses, cerebral vascular accident, myocardial infarction, and death.⁹⁹ In fact, in athletic performance studies, the most consistent finding is increased heart rate. Haller and Benowitz⁹⁹ in 2000 critically evaluated the 140 adverse events reported to the FDA from 1997 to 1999 and concluded that 62% of the adverse events reported were definitely or possibly related to the drug. In that series, 10 users were younger than 18 years, and there were 10 deaths and 13 cases of permanent disability. These included a 22-year-old man who was taking Ripped Force and sustained a cardiac arrest and was left with a permanent neurologic disability and a 15-year-old girl who was taking Ripped Fuel and sustained a fatal arrhythmia.

Legal/Sports Aspects

In 2004, ephedrine was the first supplement removed from the market by the FDA since the 1994 supplement act. However, in April 2005 a US District Court judge ruled to overturn the ban, stating that the FDA had not proved that a 10-mg dose was dangerous. She ruled that “[the prior ban] would be directly contrary to the statutory language placing the burden of proof on the government… .” It is likely that this legal battle will continue with possible appeals by the FDA, although this ruling may open the door to ephedrine's return to the supplement marketplace. The International Olympic Committee, NCAA, Major League Baseball, National Basketball Association, and National Football League all have banned the systemic use of ephedrine products.

Incidence

The NCAA has documented that its athletes in 2001 were using ephedra products earlier than in the past, with just >60% beginning use before college.⁴⁸ The work of Kayton et al⁷¹ in 2002 supported this claim, finding that among 270 high school athletes, 26% of girls and 12% of boys had tried ephedrine products. The NCAA data from 2001 reported a 3.9% incidence of ephedrine use in the past 12 months for men and women. When female sports were examined, there were marked increases from 1997, with 8.3% of gymnasts using ephedrine and 11.8% of ice hockey players using the drug compared with 1.1% and 0% rates 4 years earlier.⁴⁸ An even more recent look at collegiate use was published in 2004⁹⁸, which examined 5 male ice hockey Division I teams and found that 38% used ephedrine and 46% using pseudoephedrine in cold remedies, hoping to boost performance.