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Ergogenic Aids In the context of sport, an elgogenic aid can be broadly dejined as a technique or substance used for the purpose of enhancing performance. Ergogenic a i d have been classzj?ed as nutritional, pharmacologic, physiologic, or psychologic and range from use of accepted techniques such as carbohydrate loading to illegal and unsafe approaches such as anabolic-androgenic steroid use. The eflcacy of many of these techniques is controversial, whereas the deleterious side effects are clear. nepurpose of this article is to review the epidemiology, administration, eficacy, pharmacology, and side efects of commonly used ergogenic: aids. Physical therapists should be able to recognize the signs of ergogenic aid abuse in inditliduals under their care, and they should be aware of the side @cts of these aids. Moreover, the physical therapist can serve as a resource-forthose individuals seeking information on the risks and benejits of ergogenic aids. (Thein LA, Thein JM, Landy GL. Ergogenic aids. Phys n e r . 1995;75426- 439.J Lori A Thein Jill M Thein Gregory L Landry Key Words: Ergogenic aids, Pharmacology, Sports medicine, Sports physical therapy, stmids. Many athletes have turned to ergogenic aids in hopes of achieving an edge on their opponents. The term "ergogenic" means "tending to increase work" and, in the context of sport, includes techniques used to increase energy production and performance. Nutritional and psychologic ergogenic aids continue to be used regularly and safely. The use of carbohydrate loading, vitamins, electrolyte solutions, ritual preparation procedures, visualization, and stress management techniques receives little attention in the popular press, but these can be considered ergogenic aids. The ergogenic aids receiving the greatest attention in the last several decades are the pharmacologic and physiologic aids. Anabolic-androgenic steroids, blood doping, erythropoietin, human growth hormone, clenbuterol, and caffeine are some of the ergogenic aids currently used by athletes attempting to achieve superior performance. Attempts to gain competitive advantages over competitors is not a new phenomenon. The term "doping" has roots in a South African dialect when it referred to a liquor stimulant used in Herbs and religious ~eremonies.~ mushrooms were consumed by ancient Greek Olympic athletes in attempts to improve their perf~rrnance.~ LA Thein, PT, SCS, ATC, is Physical Therapist and Associate Lecturer, Department of Kinesiology, Physical Therapy Program, University of Wisconsin Sports Medicine Center, 3313 University Ave, Madison, Wl 53705 (USA). Address all correspondence to Ms Thein. JM Thein, PT, ATC, is Physical Therapist, Outpatient Orthopedics, University of Wisconsin Hospital, 600 Highland Ave, Madison, WI 53792. GL Landry, MD, is Assistant Professor, Department of Pediatrics, Head, Section of Sports Medicine, and Head Medical Team Physician, University of Wisconsin Medical School, 600 Highland Ave, Madison, W 53792. Physical Therapy / Volume 75, Number 5 / May 1995 In the 19th century, the French concocted uin mariani, a drink mixture of coca leaves and wine, which reportedly reduced fatigue and hunger senIn sation during prolonged a~tivity.3,~ the late 1800s, marathon runners frequently drank alcohol during races. Brandy, champagne, and another then-popular "stimulant,"strychnine, were used by American athletes.3 In the 20th century, the use of stimulants in the 1952 Olympic Winter Games, followed by suspicion of anabolic steroid use by the soviet athletes in 1954, focused attention on the use of ergogenic aids.*The 1960s saw a dramatic increase in drug abuse, with amphetamines implicated in the deaths of several cyclists.' The apparent widespread use of anabolic steroids at the 1964 Olympics was severe enough to warrant drug testing at the 1968 Olympic Games.5 Improvements in detection using mass spectrometry and gas chromatography resulted in the disqualification of 19 athletes from the Pan-American Games in 1983, and 426 / 95 in the surrender of a silver medal by Martti Vainio (1984 Olympic Games) and a gold medal by Canadian Ben Johnson (1988 Olympic game^).^,^^^ scriptions of anabolic steroids annually in the United States.14Illicit use, however, results in a much larger and untold number of annual usages. Use of ergogenic aids by patients being treated by physical therapists might affect the patients' response to treatment. Side effects of some ergogenic aids can affect heart rate, blood pressure, or other physiologic measures. Individuals using injectable drugs are at risk for disease transmission from shared needle~.~.9 Adolescents and their parents often look to physical therapists providing sports physical therapy services at local schools for information on ergogenic aids. The physical therapist can be a valuable personal and community resource for facts about ergogenic aids. Physical therapists may treat individuals who use anabolic steroids. Although some of these individuals may be taking steroids legally for medical purposes, it it more likely that patients will be t a h g these drugs illicitly. Knowledge of anabolic steroid side effects can help the physical therapist to recognize signs of abuse, and to educate the patient about the longterm deleterious effects of anabolic steroid use. "Ergogenic aids" is a broad category of topics (including physiologic, phannacologic, psychologic, and nutritional'), and the choice of substances used as ergogenic aids changes with improvements in technology and detection procedures. The list of techniques and substances used as ergogenic aids is too extensive for a complete discussion within this article The purposes of this article are to present several commonly abused agents and techniques, to examine their potential risks and benefits, and to discuss drug testing procedures. Phannacologic Ergogenic Aids Anabolic-Androgenic Steroids Anabolic steroids are synthetic derivatives of the male hormone testosterone. These androgens are prescription drugs that have legitimate, therapeutic uses. They are prescribed for children and adolescents to treat delayed puberty, aplastic anemia, and hypogonadism.l0>" In the adult population, steroids are used successfully to treat certain types of anemias, hereditary angioedema, some gynecologic conditions, protein anabolism, and male hypogonadism. Additionally, they may have a role in the treatment of osteop0rosis.~~J3 Medical indications account for fewer than 3 million pre- Epidemiology. The use of anabolic steroids for nonmedical purposes is not a new phenomenon. The first reported anabolic steroid use as an ergogenic aid occurred in 1954, and use became widespread in the athletic community by 1964.l3Although anabolic steroid use by athletes has been in existence for more than 40 years, data from substance use surveys is relatively new. The first reports in the early 1970s revealed that 2.5% of Arizona high-school male athletes15 and 15% of Arizona State University athletes used anabolic steroids.16Data have demonstrated that anabolic steroids are becoming increasingly popular among high-school athletes and nonathlete~.l5.~7-~0 In a 1988 nationwide survey, Buckley et all7 found that 6.6% of 3,403 male high-school seniors were using anabolic steroids, and 35.2% of these seniors were nonathletes. Of the steroid users, 38.3% reported first using anabolic steroids at age 15 years or younger, and another one third of the population had started by age 16 years. Steroid users reported using cycles of steroids lasting 6 to 12 weeks, and 40% of the steroid users had completed five or more cycles. "Stacking," or using more than one type of anabolic steroid concurrently, was practiced by 44% of the respondents, and 38.1% of the steroid users had used both oral and injectable methods of adrnini~tration.~~ Similar results were noted in an Arkansas study, where 11.1% of the 853 male 1lth-grade students surveyed reported past or present use of anabolic ste- r o i d ~Of . ~the ~ 1,881 Georgia highschool students surveyed in 1993, 6.5% of the boys were taking anabolic steroids, with one fourth admitting to sharing needles to administer the drug.9 A recent sunrey of 3,047 highschool freshmen and seniors in Illinois revealed that 3% of the males and O.Y?of the females admitting use of anabolic steroids.20 Of those individuals using steroids, 64% were athletes, 26% reported using a stacking technique, and 21% listed a teacher/coach as the main source who got them interested in using steroids. Twentyone percent of steroid users started using steroids at age 15 years, 19?? started at age 14 years, and 7% started before the age of 10 years. The National Collegiate Athletic Association (NCAA) has been collecting data on the use of anabolic steroids in collegiate athletes since 1985. Anabolic steroid use among male football players dropped from 9.7% of the players in 1989 to 5.0% of the players in 1993." Male basketball players showed an increase in use from 1.6% to 2.6941, and female basketball players showed an increase in use from 0.8% to 1.5%. For a list of the most commonly used anabolic steroids, see Table 1. Pharmacology and physiologic effects. All anabolic steroids are derivatives of the male sex hormone testosterone. The synthetic agents have a core steroid structure that gives them both anabolic (tissue building) and androgenic (masculinizing) e f f e ~ t s . ~ ~ ~ ~ Physiologically, the anabolic and androgenic effects are inseparable. When the hormone binds with receptors in various tissues, the same type of receptors produce anabolic and androgenic effects. In some sites throughout the body, the hormone will bind and produce anabolic effects, whereas at other sites, it will bind and create androgenic effects. The most appropriate name for these compounds is "anabolic-androgenic steroids," but the term is frequently shortened to "anabolic steroids." Attempts to enhance the anabolic effects while diminishing the androgenic effects have brought about the creation of over 40 chemical Physical Tht:rapy / Volume 75, Number 5 /May 1995 Table 1. Commonly Used Anabolic ~ t e r o i d s " ' ~ ~ ~ ~ Generic Name Brand Name Derivative -- Oral Ethylestrenol Maxibolin Fluoxymesterone Halotestin Methandrostenolone Dianabol Methyltestosterone Metadren, Oreton Methyl Oxymetholone Anadrol-50 Stanozolol Winstrol Injectable 19-Nortestosteroneester Nandrolone Deca-Durabolin Nandrolone phenor~ouibate Durabolin 19-Nortestosterone Testosterone cypionate Depo-testosterone Testosterone ester Testosterone propionate Oreton Testosterone ester Testosterone enanthate Delatestryl Testosterone ester modifications of the core ster0id.l When taken orally or parenterally in its origins[ state, testosterone is quickly degraded by the liver, and blood levels necessary to achieve anabolic effects are not sustained. Consequently, three modifications of the testosterone molecule have been made (designated as types A, B, and C ) and demonstrate increased effect i v e n e s ~These . ~ ~ are esterification of the 17P-hydroxylgroup (type A), alkylation of the 17a-position (type B), and moddication of the ring structure of the steroid (type C). Oral preparations are usually types B and C, whereas parenteral compounds are usually type A.25 Anabolic steroids work to increase protein synthesis, lean body mass, and nitrogen balance via several mechan i s m ~Many . ~ ~ cells in the body, including skeletal muscle, possess receptors that bind testosterone or similar hormones. A steroid-receptor complex is formed. causing synthesis of enzymes, which in turn causes increased protein synthesis in the cells. One of the enzyme systems induced by this process is the ribonucleic acid (RNA)polymerase system. Biochemically, RNA polymerase promotes cellular protein metabolism and synthesis, causing the anabolic action leading to increased muscle, lean body mass, and ~trength.7JOJ~-~~ Anabolic steroids may also enhance lean body mass via an anticatabolic effect.27During episodes of stress, such as intense exercise, the body releases glucocorticoids, which have a catabolic effect on body tissue^.^ Anabolic steroids compete with glucocorticoids for receptor sites and inhibit protein degradationlo Anabolic steroids also promote nitrogen retention by shifting the nitrogen equilibrium to the positive side for better utilization of ingested protein. This is a temporary phenomenon due to the body's homeostatic mechanisms. To obtain the full benefit of this effect, athletes must maintain a diet high in calories and protein while taking anabolic steroids.ll Finally, anabolic steroids may increase strength and muscle mass through their psychologic effect. Athletes taking anabolic steroids frequently report episodes of euphoria, increased aggressiveness, and decreased fatigue, which may allow them to train at a higher intensity for a longer duration.lo Administration. Anabolic steroids may be taken orally or parenterally. Orally ingested steroids are well absorbed from the stomach, excreted fairly rapidly from the body due to their short half-lives, more toxic than injectable steroids to the liver, and Physical 'Therapy / Volume 75, Number 5 /May 1995 highly potent. Injectable steroids are characterized by delayed uptake from the body, slower excretion, increased detectability in dnig tests for longer periods of time, less liver toxicity, and less potency than oral steroids.ll Injectable preparations can be detected for a month after discontinuation, whereas oral doses are detectable up to 14 days after discontinuation. Athletes rely heavily on rumors or anecdotal experiences to guide their dosage of anabolic steroids. Athletes frequently use the technique referred to as "stacking," or the concomitant use of two or more anabolic steroids at high doses, although there is no scientific basis of this t e c h q u e . The combination may involve both injectable and oral forms. Athletes may adhere to a pyramid-type of schedule, starting with a low dosage, increasing to peak usage (sometimes staclung three to five drugs), and slowly tapering usage over 4 to 18 weeks. This pyramid-type schedule is followed by a drug-free period of several weeks to months, which is referred to as "cycling."26During peaks of pyramid schedules, athletes may be taking 10 to 100 times the normal therapeutic dosage.1° Burkett et alZ8found the lowest anabolic steroid dosage in the 24 athletes they surveyed to be 350% of the usual therapeutic dosage. No scientdic evidence exists suggesting that stacking or a pyramid schedule is necessary to achieve the anabolic effects. The androgen receptors are well saturated at much lower dosages.10 Ergogenic efficacy. Studies on the effects of anabolic steroids on muscular strength provide inconsistent results. Quantitative studies of the effects of anabolic steroid use present many metholologic dficulties. The side effects of anabolic steroid use make blind studies a challenge. Participants are frequently able to guess correctly when they are in the placebo or steroid portion of the study. Moreover, the doses that can be ethically a h istered are well below those that athletes report using. After reviewing and statistically analyzing 25 well-documented studles, Haupt and Rovere7 concluded that improvements in muscular strength will result from anabolic steroid use if the following criteria are met: (1) The athlete must have been intensively trained in weight lifting immediately prior to the steroid regimen and must continue with intense weight lifting during the steroid regimen; (2) the athlete must maintain a high-protein, highcalorie diet; and (3) strength must be assessed with a single-repetition, maximal-weight technique using the specific exercises with which the athlete trains, as opposed to single-joint, isolation-testing techniques. These criteria are partially supported by Tingus and Carlsen," who found no significant improvement in the growth, contractile strength, or endurance of hind-limb skeletal muscles of rats receiving a continuous lnfusion of stanozolol. The authors concluded that anabolic steroids had no ergogenic effect in the absence of high-intensity exercise or muscle atrophy. Additionally, Crist et also found no improvement in isokinetic power measurements following administration of anabolic steroids. In a recent meta-analysis, Elashoff et alsl reviewed 30 studies evaluating the effects of anabolic steroids on muscle strength. Fourteen of these studies were not included in the meta-analysis for one or more of the following reasons: (1) There was no placebo group, (2) there was a failure to randomize subjects into groups, (3) strength measurements were not objective, or (4) the percentage change in strength could not be ascertained. Of the remaining studies, the statistical analysis was unclear, not stated, or performed incorrectly in 11 studies. Data analysis in 9 studies with adequate available information demonstrated a slightly greater strength improvement in the anabolic steroid-treated group of trained individuals, with a mean dBerence of 5%. No evidence existed to support enhanced muscle strength in untrained individuals. Weight gain is commonly associated with anabolic steroid use and has prompted study of body composition changes. A review of the literature indicates that athletes talung anabolic steroids for 3 to 12 weeks gain an average of 2.2 kg more weight than their counterparts receiving a placebo.32833 Whether these gains reflect muscle mass increases or fluid retention remains unclear. Although radiographic studies and body-density measurements indicate increases in muscle size and lean body mass, the concurrent increase in total body potassium and nitrogen are disproportionate to the weight gain." Therefore, it is unclear whether weight gain is due to increases in normal muscle, other lean tissues, or intracellular fluid.26 Side effects. Although the potential benefits associated with anabolic ster i d use remain questionable, the immediate and long-term side effects are well established. Anabolic steroids have been linked to a myocardial infarction in a 22-year-old world-class weight 11fter3~and to a lefthemispheric cerebrovascular accident (CVA) in a 34-year-old body builder.35 The death of National Football League (NFL) star Lyle Alzado fmm a brain tumor in 1992 raised concern about the risk of cancer with chronic use of steroids. Steve Courson, another retired NFL star, is speaking publically about steroid abuse, which caused his cardiomyopathy.ll More common adverse effects involve the hepatic, endocrine, musculoskeletal, cardiovascular, immune, reproductive, and psychological systems.36.37 The extensive metabolism of the oral forms of anabolic steroids leads to sigmficant hepatotoxic effects. The abnormalities in liver function caused by anabolic steroids are usually reversible upon discontinuation of the druge26Oral anabolic steroids may cause cholestasis, jaundice, and, seldornly, a pathologic condition associated exclusively with oral anabolic steroids, peliosis hepatis. Pelosis hepatis is the formation of blood-filled sacs in the liver, which may rupture and cause fatal hem0rrhage.~OJl.~6 Creagh et a138 reported the fatal rupture of a hepatic tumor in a 27-year-old body builder who had been taking oral anabolic steroids. Two cases of hepatocellular carcinoma have been reported in otherwise healthy athletes who used anabolic steroids.39 Anabolic steroids have dramatic effects on the reproductive system owing to their androgenic effects. Significant decreases in plasma testosterone have been demonstrated in males taking from 15 to 150 mg/d of anabolic ster0id.N-~2The exogenous androgen creates testicular atrophy, which may be irreversible (chemical castration).ll Currently, it is thought that anabolic steroids affect plasma hormone levels via action at the pituitary and hypothalamus. Exogenous anabolic steroid replaces testosterone in the negative feedback system at the level of the pituitary and hypothalamus, resulting in a decreased production of gonadotropins. Reduction in serum concentrations of pituitary interstitial cellstimulating hormone (ICSH) and follicle-stimulating hormone (FSH) causes a decrease in testosterone production from the te~tes.lO~~6,~Z Physical changes associated with anabolic steroids and the reproductive system include prostate enlargement, decreased sperm counts by W h or more, testicular atrophy, impotence, and gynecomastia.l1 Sperm counts usually return to normal after discontinuing the drug, yet male infertility has been reported up to 7 months after cessation of steroid use.1° Gynecomastia is a well-known side effect of anabolic steroids and is characterized by a subareolar, bunonlike unilateral or bilateral plaque of ti~sue.~3 Gynecomastia is caused by the estrogens estradiol and estrone, which are produced when androgens are converted in extraglandular tissue. Estradiol levels in athletes who are stacking steroids can be seven times the normal level of ovulating women.lO Attempts to use estrogen inhibitors, such as human chorionic gonadotropin or tarnoxifen, have proven to be unsuccessful. In extreme cases, the development of breast tissue is not totally reversible, and mastectomy may be required.43 Physical Therapy / Volume 75, Number 5 / May 1995 Evidence of increased musculotendinous injury has been noted in the anabolic steroid user. Miles et aP4 discovered that tendons in exercised, steroid-treated animals became less elastic and more prone to injury. With increased strength in the muscle and decreased strength in the tendon, the athlete is more likely to develop strains or ruptures. In children, anabolic steroids cause premature closure of the epiphyses, resulting in decreased adult height.11 Use of anabolic steroids has been linked to alterations in lipid profiIes.l2J4,26,*5The most consistent side effects of anabolic steroid use are a significant rise in total serum cholesterol level and a decrease in highdensity lipoprotein (HDL). Reduced HDL levels are such a consistent finding that it has been suggested that use of HDL levels to detect steroid use may be useful as a less expensive screening test than urinalysis.1° Webb et a145 studied 14 body builders during training with and without the use of anabolic steroids. Self-administration of anabolic steroids by these athletes reduced HDL concentrations by greater than 50%.45Increases in lowdensity lipoproteins (LDL) and a tripling of the LDLIHDL ratio were also observed after 2 months of steroid use. This effect did not appear to be permanent. The HDL concentrations returned to near normal 7.3 months after steroids were discontinued. During the time these athletes did not use drugs, they had high HDL levels and relatively low LDL levels. This observation was similar to that of Goldberg et al," who reported that a group of steroid-free athletes demonstrateed favorable changes in lipid levels with a weight training program. C0sti11~~ reported signdicantly lower HDL concentrations in athletes using anabolic steroids when compared with untrained men and strength-trained men who were not using these drugs. This decline in HDL concentration with anabolic steroid use was reversible within 3 to 5 weeks after cessation of steroid use. Although the underlying mechanism of the decrease in HDL levels with anabolic steroid use is unclear, Costill et a147suggest that the main effects of androgens on lipoproteins are the consequence of an inhibition of apoprotein A synthesis, the main apoprotein in HDL-C. Although studies have demonstrated a direct relationship between low levels of HDL and coronary artery disease, the effect of long-term administration of anabolic steroids on the development of athlerosclerotic coronary artery disease has not been determined.26.47 Psychologic side effects of anabolic steroids include euphoria, aggressiveness, irritability, nervous tension, changes in libido, mania, and psychosis. Up to 80% of steroid users are aware of overly aggressive and violent behavior during periods of high consumption of steroids.ll Studies suggest that marked affective or psychotic symptoms may sometimes occur in individuals who are taking anabolic steroids. In a study of 41 body builders, 9 (22%) exhibited full affective syndrome in accordance with the Diagnostic and Statistical Manual of Mental Disorders (DSM-111-R) criteria, and 5 (12%) reported psychotic symptoms with anabolic steroid use. Delusions, hallucinations, anorexia, hyperactivity, and grandiosity have been correlated with anabolic steroid ~ s e . ~Pope ~ , ~and 9 Katz49describe case reports of 3 men with no premorbid psychiatric histories who cornrnited violent crimes (including murder) while taking anabolic steroids. Athletes may also develop clinical depression while withdrawing from steroids. This can be a significant problem given the on again-off again cycling pattern of anabolic steroid use. Anabolic steroid use is becoming more popular among females, and the adverse effects in women are not well documented. Strauss et a150 studied 10 weight-trained women who consistently used anabolic steroids. The women used stacking and cycling techniques, taking up to nine times the manufacturers' recommended dosages. Perceived side effects included lower voice, enlarged clitoris, increased libido, oligomenorrhea or amenorrhea, increased aggressiveness, acne, increased growth of body hair, and decreased body fat. Side effects Physical Therapy / Volume 75, Number 5 May 1995 such as enlarged clitoris and deepening of the voice are irreversible.26 Regulation. Federal and state effofls have increased in attempts to control the illegal sale and distribution of anabolic steroids. Several states have passed legislation making some ambolic steroid transactions illegal and subject to felony charges.14Anabolicandrogenic steroids are banned by the US Olympic Committee (USOC), the International Olympic Committee (IOC), the NCAA, and the NFL. Human Growth Hormone Human growth hormone (GH) is identdied as a family of structurally related proteins synthesized by anterior pituitary somatotropes, of which the primary monomer is a 22,000-d, 191-amino acid polypeptide.jl Growth hormone is used for replacement therapy in children who are GH deficient. Additionally, GH is being studied for used in Turner's syndrome, children with delayed growth, and short children with intrauterine growth retardation or similar disorders.5' Pharmacology and physiologic effects. The human pituitary contains between 5 to 10 mg of GH, with daily production of 0.4 to 1.0 mg in men and with slightly higher rates in adolescents and women.'j Serum levels vary throughout the day owing to its intermittent, pulsatile release, but average 0.5 to 3.0 pg/L and are affected by a number of factors. The half-life of GH ranges from 17 to 45 minutes, and proteolysis into a more bioavailable two-chain form takes place in the skeletal m~scle.~,5~153 The secretion of GH is controlled through a feedback loop involving GH-releasing hormone (GHRH) and somatotropin-release-inhibitinghormone (SRIH). Growth hormone release can be affected by multiple factors, including sleep, exercise, stress, hypoglycemia, alpha-adrenergic agonists, beta-adrenergic antagonists, GH levels, and dopaminergic agonists (Tab. 2).2.i2-55Growth hormone increases in response to hypoglycemia and exercise, and the largest GH surge Table 2. whereas GH-mediated growth occurs as a result of increases in the rate and translation of existing RNA.52,54 Factors Affecting Growth Hormone Secretiona Stimulative Suppressiveb Growth hormone has potent effects on carbohydrate and lipid metabolism, Functioning to decrease glucose and protein metabolism by shifting oxidative metabolism toward the use of fatty acids.53 Administration of GH results in decreased peripheral fat stores, increased hepatic lipid stores, and increased plasma free fatty acids (FFA).52-5+ Because of its lypolytic and anabolic effects, GH has been abused by body builders attempting to decrease fat and increase lean body ma~s.5~ Physiologic Sleep Postprandial hyperglycemia Exercise Elevated free fatty acids Stress (physical or psychological) Postprandial hyperarninoacidemia Postprandial hypoglycemia (relative) Pharmacologic Hypoglycemia: Hormones: Absolute: insulin or 2-deoxyglucose Somatostatin Relative: postglucagon Sornatomedin C (IGF-1) Hormones: Growth hormone Peptides (GRH, ACTH, a-MSH, vasopressin) Progesterone Estrogen Neurotransmitters: Neurotransmitters: a-Adrenergic agonists (clonidine) a-Adrenergic antagonists (phentolamine) p-Adrenergic antagonists (propranolol) P-Adrenergic agonists (isoproterenol) Serotonin precursors (5-hydroxytryptaine) Serotonergic antagonists (methysergide) Dopaminergic agonists (L-dopa, apomorphine, bromocritine) Dopaminergic antagonists (phenothiazines) GABA agonists (muscirnol) Cholinergic (muscarinic)antagonists (pirenzepine) Pathologic Protein depletion and starvation Obesity Anorexia nervosa Hypothyroidism and hyperthyroidism Chronic renal failure Acromegaly: dopaminergic agonists Acromegaly: TRH GnRH "GRH=growth-hormone-releasing hormone, ACTH=adrenocorticotropic hormone, MSH= melanocyte-stimulating hormone, GABA=gamma-aminobutyric acid, TRH= thyrotropin-releasing hormone, GnRH=gonadotropin-releasing hormone, IGF=insulinlike growth factor. (Reprinted with permission from Frohman LA. Diseases of the anterior pituitary. In: Felig P, Baxter JD, Broadus AE, Frohman LA, eds. Endocrinology and Metabolism. 2nd ed. New York, NY: McGrawHill Book Co; 1987:268.) ' ~ u ~ ~ r e s s ieffects v e of some factors can be demonstrated only in the presence of a stimulus occurs approximately 60 to 90 minutes after the onset of sleep.53 Following GH release, the pituitary becomes unresponsive to further stimulation for several hours, thus providing a negative feedback loop. This response is true of both endogenous release and exogenous administration of GH. The result of exogenously adrninstered GH is the down-regulation of endogenously released GH.' The primary function of GH is to promote growth via the generation of somatomedins, spechcally insulinlike growth factor (IGF-1). Growth hormone and IGF-1 promote anabolism, facilitating muscle, bone, and cartilage growth. Increased protein deposition (anabolic effects) occurs owing to facilitation of nearly all aspects of amino acid uptake and protein synthesis by the cells, with concurrent reduction of protein catabolism.56 The GHmediated growth is dfierent from the growth that occurs as a result of work. New RNA must be synthesized for exercise-induced muscle growth, Administration. Therapeutic dosages of GH for individuals with GH deficiency range from 0.06 mg/kg to 0.1 mg/kg three times weekly, depending on the spechc medication2 Recombinant human growth hormone (rGH) is currently used because of cases in which Creutzfeldt-Jakob disease was spread via use of the naturally occurring hormone.57 Two forms of rGH are currently available, one containing the entire natural sequence and a second containing an additional methionyl amino acid re~idue.5~ Athletes have reported taking up to 20 times the therapeutic dosage in hopes of gaining some of the effects of anabolic steroids without being dete~ted.5~ Some athletes take propanolol, vasopressin, clonidine, and levodopa to stimulate exogenous GH secretion.53 Because of the physiologic negative feedback loop, however, it is likely that the body would autoregulate the GH levels to the proper physiological amount. Injecting large quantities of GH would increase the circulating levels and concentrations of GH, leading to the anecdotal reports of increases in muscle bulk and ~trength.5~ Ergogenic efficacy. The observed muscle size increase without simultaneous strength increase in individuals with acromegaly prompted the study of the effects of a concurrently administered GH and resistive exercise program. Yarasheski et a15"valuated the effectiveness of exogenously administered GH on muscle growth in a Physical The]rapy / Volume 75, Number 5 / May 1995 group of 16 untrained male subjects. After 12 weeks of training in combination with 5-d/wk GH injections, the treatment group demonstrated protein balance when compared with a placebo group. Quadriceps femoris muscle protein synthesis rate, torso and limb circumferences, and muscle strength, however, were not increased. The authors concluded that the increase in fiat-free mass (FFM) was due to increases in lean tissue other than skeletal muscle, but they d ~ d not spectulate where these increases might have occurred. Moreover, the authors concluded that resistance training supplemented by GH did not further enhance muscle anabolism and function. Christ et aI6O studied the effects of GH on body composition and endogenous secretion of GH and IGF-I in adults. Following 6 weeks of resistance exercise and a high-protein diet, those subjects receiving GH demonstrated significant increases in fat-free weight and decreased percentage of body fat compared with a placebo group.G0 Changes in the fat-free weight/fat weight ratio were correlated with the relative dosage - of GH. Increases in the mass of atrophied and normal muscles have been found with the adrninistration of GH in rats. Neither improved tension development nor enhanced performance, however, were found in the nonnal or hypertrophied prohibited by the USOC, the IOC, and the NCAA. The Federal Food, Drug, and Cosmetic Act includes penalties for illegal use or distribution of human GH. Currently, the annual cost of rGH ($14,000-$20,000 for a 20-kg child) is a prohibitive factor in abuse. No medical tests exist for the detection of human GH. Clenbuterol Clenbuterol is a beta2-adrenergic agonist that has proposed ergogenic properties resulting from central nervous system (CNS) stimulation. It is a sympathomimetic drug that has a peripheral excitatory action on smooth muscle, a cardiac excitatory function, and metabolic and endocrine actions.S2 These drugs are used primarily for their ability to produce relaxation in smooth muscle. The beta,-agonists are widely used as bronchodilators for the prevention and treatment of symptoms of exercise-induced asthma and for relaxation of the uterus in premature labor (Tab. 3). - Table 3. Major Classijications of Receptor Types and Action ~ - - ~ Receptor Action a-1 Constriction of blood vessels to skin, mucous membranes muscle^.^^^^^ Side effects. Adverse effects of large quantities of GH in adults include acromegaly with associated myopathy, peripheral neuropathy, glucose intolerance, increased plasma cholesterol and triglyceride concentrations, coronary artev disease, and cardiomyopathy.2,27,52,54 In prepubescent athletes, excessive quantities of GH result in gigantism. The musculoskeletal and cardiac effects associated with excessive GH use may be irreversible, even after discontinuation of the hormone. Moreover, needle sharing for intramuscular administration carries the risk of disease transmission. Phannacology and physiologic effects. Clenbuterol is a potent growth-promoting beta-agonist with peripheral and central effe'ects.65These effects include an increase in heart rate and cardiac contractility, an increase in the rate of glycogenolysis in the liver and muscle, liberation of FFA, and enhancement of pituitary hormone release.65Sympathetic stimulation results in peripheral excitation of smooth muscle of the blood vessels supplying the skin and mucous membranes and in ~nhibitionof smooth muscle of the blood vessels supplying the skeletal muscle, gastrointestinal tract, uterus, bladder, and bronchial tree. Central effects also occur from sympathomirnetic drugs and include respiratory stimulation, increased alertness, and decreased appetite.(*l Pupillary dilatation Relaxation of smooth muscle in gut a-2 Inhibits further release of norepinephrine P- 1 Increases heart rate and contractility P-2 Dilatation of blood vessels to skeletal muscle Relaxation of bronchial smooth muscle Relaxation of smooth muscle to uterus p-3e Increasedmetabolic rate The potential ergogenic properties of clenbuterol stem from its array of sympathomirnetic effects. Increased lipolysis and decreased lipogenesis are dramatic effects noted with chronic beta-agonist treatment.63a65," This process increases fat availability for energy, theoretically increasing endurance. Increased glycogenolysis from the liver may increase carbohydrate availability, and increased skeletal muscle blood flow may enhance the peripheral delivery system. Increasedthermogenic effect Decreased appetite Regulation. Human GH, synthetic GH, and GH-releasing factors are all The anabolic effects of clenbuterol are purported to include the prevention of muscle atrophy, an increase in lean body mass, and a decrease in body fat.63 Clenbuterol, therefore, has been termed a "repartitioning agent," or an agent that manipulates growth and body composition, enhancing the deposition of body protein and decreasing fat.64The beta2-agonistshave been studied extensively in animals in attempts to increase lean body mass and decrease body fat in animals bred for consumption. These substances are also being evaluated for their role in the treatment of obesity because of their repartitioning effects and because of the thermogenesis seen with betaagonist treatment.63a65 "Mects brown (fat) cells Physical Therapy /Volume 75, Number 5 /May 1995 Protein anabolism is a consistent finding with clenbuterol administration. This protein increase may be the result of increased synthesis or decreased catabolism, or both. The proposed cellular mechanisms stem from the control of protein metabolism via increased calcium transport, increased cyclic adenosine monophosphate (CAMP) levels, and an activation of protein kinase.65 Both indirect (insulin release, increased peripheral blood flow, pituitary hormones) and direct (modulators of protein turnover, contractile activity) mechanisms may participate in the hypertrophy process65 Administration. Clenbuterol hydrochloride is used as a bronchodilator in the management of asthma in usual doses of 20 pg two or three times daily by It is available as an oral preparation with a plasma half-life of 34 hours and a slightly longer tissue half-life. Changes in muscle growth can be obsewed within 2 days of treatment, with the maximum growth within 8 days65 Attenuation takes place after approximately 14 days, likely due to beta-receptor saturation and subsequent receptor down regulation. Rothwell et a169 demonstrated a 50% reduction in muscle beta-receptor density after 18 days of chronic clenbuterol treatment in rats. Intermittent administration of betaagonists has been shown to attenuate this effecL65 For this reason, athletes often "cycle" clenbuterol, taking it on and off in 2-day cycles. This cycle is generally continued for 8 to 10 weeks, followed by 10 to 12 weeks without the drug." Currently, no research supports this cycling schedule, although, as with many ergogenic aids, anecdotal reports exist. Anecdotal reports suggest that athletes often combine clenbuterol with other hormones such as anabolic steroids or GH to exponentially increase its effects, a practice that is supported by animal research.6" Ergogenic efficacy. Most studies of ergogenic efficacy have been performed on animals, although studies on humans with obesity are being initiated. Anabolic effects have been found, with 1@/o to 20% increases in muscle weight noted after 1 to 2 weeks of clenbuterol administration in rats.65,70Rothwell and Stock67 found that a daily injection of clenbuterol (1 m g k g of body weight) produces a 12% weight gain and a 13% increase in the body proteinfat ratio in rats. Administration of beta,-agonists appears to promote fiber-specific (fasttwitch glycolytic) muscular hypertrophy, with increases in the crosssectional area reported to be 1@/0to 50% in a n i m a l ~ . ~Maltin , ~ 5 et aF4 found hypertrophy in the fast-twitch glycolytic fibers in animals treated with a daily dose of clenbuterol, and a combination of clenbuterol and GH resulted in hypertrophy in fast-twitch glycolytic, fast-twitch oxidative glycolytic, and slow oxidative fibers. Muscle RNA was increased consistent with the increase in muscle protein, and clenbuterol appeared to enhance protein anabolic effects via a depression of protein degradation rates, with little or no change in protein synthesis. Although other researchers have found similar anabolic changes, these effects were the result of increases in protein synthesis71 or increases in both synthesis and d e g r a d a t i ~ nInjection .~~ of clenbuterol (0.125 mg/kg of body weight) in rats resulted in increases in CAMP,blood lactate, muscle mass, and protein synthesis as well as decreases in muscle glycogen.67The increase in muscle mass was attributed to the protein synthesis increase, although the authors noted that the results may have been partly due to an altered rate of muscle protein degradati0t-1.~~ Other beta,-agonists (albuterol, salbutamol, cimaterol) have been studied to determine the potential ergogenic effects of these drugs. Morton et a173 studied the acute effects of a 200-pg dose of salbutamol inhalant on several physiologic variables and performance in high-level, nonasthrnatic athletes. The authors found no Merences in any measurements between treatment and placebo conditions. In contrast, Martineau et a174studied the chronic effects of a 3-week, 16-mg/d administration of an oral form of sustainedrelease salbutarnol. The treatment group demonstrated increases in quadriceps femoris and hamstring muscle group strength compared with the control group. The single-dose and chronic-treatment effects, therefore, must be distinguished, and they may help explain the differences in study results. Length of treatment, dosage, route, and timing of clenbuterol administration can affect results. Side effects. Side effects of clenbuterol use are slmilar to those of any beta,-agonist. Tremor, tachycardia, anxiety, palpitations, headache, nausea, anorexia, and insomnia are common complaints. Additionally, potentially serious side effects include cardiac muscle hypertrophy and dysrhythrnia, myocardial infarction, or stroke.66 Regulation. All oral beta-agonists, including clenbuterol, are banned by the IOC, the USOC, and the NCAA. Currently, oral clenbuterol is available only for veterinary use in the United States, whereas other oral betaagonists are widely used. Urine levels of 0.5 ng/mL are detectable by gas chromatography and mass spectrometry 2 to 4 days after the last dose. Erythropoietin (EPO) is a glycoprotein produced by the kidney that functions to regulate red blood cell (RBC) production. This 36,000-d, 166-amino acid glycoprotein has a half-life of 6 to 9 hours. Approximately 90% of EPO is synthesized in the renal cortical cells, whereas the remainder is synthesized in extrarenal sites, primarily the live ~ - Recombinant . ~ ~ , ~ ~ EPO (rEPO) was first available in Europe in 1987 and subsequently in the United States in 1989. Recombinant EPO is nearly identical to natural EPO both biochemically and immunologically, although some minor differences exist. Commercial production utilizes recombinant deoxyribonucleic acid (DNA) technology to manufacture rEPO from Chinese hamster ovary cells. Patients with anemia from various conditions, as well as patients anticipating blood loss from upcoming surgery, can benefit from the use of rEP0.76,77 Pharmacology and physiologic effects. Erythropoietin and rEPO are used specifically by endurance athletes Physical The:rapy / Volume 75, Number 5 / May 1995 to increase aerobic endurance, with effects similar to that of blood doping. Erythropoietin is a major factor in the stimulation, proliferation, and maturation of the bone marrow stem cell, which, in turn, increases the rate of RBC pr0duction.~5Hypoxia, with a subsequent decrease in renal blood flow, or low levels of circulating hemoglobin stimulate the production and secretion of EPO by these sites. In normal bone marrow, stem cells differentiate into late burst erythroid colony forming units (BFU-E), which replicate and differentiate into early erythroid colony forming unit cells (CFU-E) and eventually into mature RBCs. This process normally takes approximately 7 days, with no new RBCs appearing for the first 2 days and with maximum RBC production reached after 5 or more days. Exogenous EPO is used in patients wlth end-stage renal disease and enhances RBC production by expanding the BFU-E and stimulating the CFU-E'~ (Figure). @-@-@ Stem vI BFU-E cell @ cr '.I\:: 0 I n I Administration. Administration of rEPO in patients with end-stage renal disease is recommended at a level of 150 U/kg three times per week with adjustmen& as necessary to achieve a response.7s The half-life of rEPO administered intravenously is approximately 5 to 11 hours, whereas the half-life is 25 hours when administered subcutaneously, depending on dosage. Absorption is slower with subcutaneous administration, with peak concentrations occurring 10 to 15 hours after administration.7679 Ergogenic efficacy. The proposed ergogenic benefits of EPO are derived from the early release of marrow reticulocytes (young RBCs), stimulation of megakarocytopoesis (platelet precursors), increased hemoglobin synthesis by KBC precursors, proliferation of BFU-E, and proliferation and dfierentiation of CFU-E cells. The resultant increase in RBCs will increase oxygen carrying capacity, thereby increasing oxygen availability to the tissues. Increased oxygen availability to the tissues al1c)ws for increased adenosine triphosphate (ATP) production and improved aerobic performance. Patients receiving 600 U/kg of body * 2s Mature RBC Figure. stimulation of red blood cell production by erytbropoeitin. BFU-E= burstforming unit-erytbmid, red cell precursor; CFU-E= colony-forming unit-erythroid, red cell precursor; Epo= erytbropoietin; RBC= red blood cell. (Reprinted zcitb permission from Wingard LB, Brody TM, LarnerJ, Scbujartr A. Human Pharmacology: MoleculartoClinical. St Louis, Mo: Mosby-Year Book lnc; 1991:860.) weight intravenously twice weekly for 21 days demonstrated a 41% greater RBC volume than did those receiving a p l a c e b ~Ekblom .~ and BerglundB1 administered rEPO to 15 well-trained male subjects at a dosage of 50 U/kg subcutaneously three times per week for 6 weeks. Results demonstrated increased hematocrit of lO?h, exercise time to exhaustion by 17%, maximal oxygen consumption by 8%, and systolic blood pressure by 8%. Physical Therapy / Volume 75, Number 5 / May 1995 Side effects. Adverse effects of EPO or rEPO are due to the increase in RBC production and are dosedependent. Hypertension and hyperviscosity (hematocrit over 55%) of the blood are two potentially lifethreatening adverse effects. Athletes are particularly susceptible to the effects of hyperviscosity due to the unpredictable clearance of rEPO from the serum and the biological effects that last for the life of the RBC (up to 434 / 103 120 days). Effects may be exacerbated during prolonged endurance events when dehydration increases the hyperviscosity. Symptoms of hyperviscosity include headache, dizziness, vertigo, tinnitus, visual changes, angina, exercise-induced claudication, encephalopathy, and s e i ~ u r e sThe .~ athlete may also experience a thromboembolic hypoxic event because of "sludging" of the blood. Several European cyclists mysteriously died (often at rest or while sleeping) between 1987 and 1990, which coincides with rEPO availability in Europe.82It has been suggested that rEPO use in these athletes produced a vascular sludging, worsened by dehydration, eventually causing coronary artery 0cclusion.~3 caffeine. Analgesics and cold preparations contain approximately 30 to 65 mg of caffeine.84The physical therapist must be aware of the action and effects of caffeine because of its widespread use and its sympathetic and diuretic side effects. results in increased neurotransmitter release and neuronal activation, regulation of hormone-induced glycogenolysis and lipolysis, and dose-specfic CNS s t i m u l a t i ~ nCentral . ~ ~ ~ ~nervous system arousal is also facilitated directly by caffeine's inhibition of adenosine receptors in the brain. Adenosine acts as a CNS depressant, hypnotic, and anticonvulsant, and caffeine's blocking of adenosine receptors increases neurotransmitter release and lowers the threshold for neuronal activati0n.~5In the athlete, the CNS stimulation may increase mental alertness and reduce fatigue. Caffeine Pharmacology and physiologic effects. Caffeine (1,3,7-trimethylxanthine) is one of three xanthine derivatives producing similar physiological responses.84-%,8'The other two derivatives, theobromine and theophylline, are found in cocoa and tea, respectively. Of the three xanthine derivatives, caffeine produces the most CNS activity and theobromine produces the least CNS activity.% After consumption, caffeine is completely absorbed from the gastrointestinal tract and reaches peak blood levels in approximately 30 to 60 minutes. Caffeine enters the brain quickly after absorption, thus producing the rapid alertness noted after c o n s u m p t i ~ n . ~ ~ The highest concentrations following absorption are found in tissues with the highest water content, primarily the skeletal mu~cle.~5 The state of hydration, therefore, can affect caffeine distribution. The half-life of caffeine ranges from 2 to 12 hours in asymptomatic adults, with an average halflife of 4 to 6 hours. Children do not eliminate caffeine as readily as adults, and the effects may last up to 3 to 4 days in this p0pulation.~6 Caffeine is the most widely consumed stimulant known today. Approximately 80% of the adult population in the United States consumes coffee or tea daily.H%offee is responsible for 90% of the caffeine consumption in the United States, totaling approximately 210 mg per person per day.85 Caffeine is also found in chocolate, soft drinks, weight-loss and cold preparations, and analgesics. Currently, the National Center for Drugs and Biologics lists caffeine as an ingredient in more than 1,000 over-the-counter pharmaceuticals.% Consequently, caffeine consumers include children as well as adults. Depending on preparation, a cup of coffee contains approximately 100 to 120 mg of caffeine, whereas a 12-02 soft drink contains 30 to 60 mg of Ergogenic efficacy. Studies examinCaffeine is proposed to exert its effects ing the glycogen sparing effect of by (1) antagonism of adenosine recepcaffeine have provided mixed results. tors:* (2) inhibition of enzyme activity Dserences in the quantity and timing such as phosphodiesterase,75 (3) alterof caffeine administration, variations in exercise protocols and subject nutriing the release or uptake of calcium from the sarcoplasmic r e t i c u l ~ m , ~ 5 > ~ ~tional status, and inconsistency in the caffeine "naivet~"of the subjects have (4) altering the calcium permeability of the sarcolemma, or (5) facilitating likely produced this disparity. Tolerneuromuscular impulse transmi~sion.~~ ance to many of the effects of caffeine Caffeine acts as a CNS stimulant, indevelops within a few days, and the creasing arousal, reducing fatigue, results of caffeine ingestion on perfordecreasing motor reaction time, and mance are highly dependent on an individual's normal quantity and changing normal electroencephalogram recordings. Excessive caffeine schedule of caffeine c o n ~ u m p t i o n . ~ usage can produce irritability, restlessHabitual caffeine consumption can ness, diarrhea, insomnia, and anxiety. attenuate heart rate and blood presInhibition of phosphodiesterase results sure, and catecholaminergic responses in elevated levels of CAMP, an importo acute caffeine administration can tant regulator of cellular functions. occur within a few days.91 Fisher et Maintenance of elevated CAMP levels aP2 found that habitual caffeine users Regulation. Blood doping of any kind, including use of EPO, is banned by the NCAA, the IOC, and the USOC.83 Unfortunately, detection of naturally occurring substances is difficult. Recombinant EPO is slightly different from EPO, and advances in technology may detect these ditferences. Assessment of the RBC age may be beneficial, as athletes abusing EPO should demonstrate a younger RBC population. Although the estimated yearly cost of legitimately obtained EPO of $5,000 to $6,000 may impede its use by some athletes, no definitive deterrents exist.83 In addition to decreasing the perception of fatigue, athletes use caffeine as an ergogenic aid because of its proposed ability to increase circulating levels of FFA and to "spare" glycogen by altering substrate utilization. Caffeine ingestion produces an increase in the plasma concentration of FFA and catecholamines and increases l i p o l y ~ i sIncreased .~~ lipolysis has been attributed to either increased intracellular CAMP,which accelerates hydrolysis of stored triglycerides, or to direct xanthine inhibition of phosphodiesterase.8' The caffeine-facilitated increases in blood EFA levels are suggested to produce shifts in substrate utilization, increasing FFA oxidation and slowing glycolysis, thereby "sparing" glyc0gen.~99% Physical Th~erapy/ Volume 75, Number 5 /May 1995 developed a tolerance to the effects of caffeine, which was negated after a 4-day withdrawal period. Costill et a189 found that elevated plasma FFA levels in seven cyclists who ingested 330 mg of caffeine resulted in a 40% decrease in the rate of muscle glycogen depletion, whereas several other researchers have failed to find an increase in FFA oxidation associated with increased blood FFA levels,'l-!'5 suggesting no change in substrate utilization.%Additionally, have found several researchers93~95~97,~ increased blood lactate levels following caffeine ingestion and exercise. Ravussin et a199 observed a higher rate of fat oxidation and decreased carbohydrate oxidation rates with increased plasma FFA levels only during the first 30 minutes of a 150-minute exercise session. Moreover, higher FFA levels did not alter substrate utilization after glucose feedings during exercise. Flinn et allo0studied the effects of a 10-mg/kg-' caffeine dose given 3 hours prior to an incremental cycle ergometer test in nine male caffeinenaive subjects. Subjects worked longer, performed more work, and exhibited higher FFA levels in the caffeine trial than during control or placebo trials. The authors concluded that caffeine was ergogenic when taken 3 to 4 hours prior to exercise in fasting subjects with diets normally low in caffeine. The effect of time of caffeine ingestion was evaluated in six trained, caffeine-naive men who consumed 10 mg/kg-' of caffeine immediately before a treadmill run to exhaustion.lol The athletes ran farther during the caffeine trial, and they had increased blood lactate and blood glucose responses at the end of exercise during the caffeine trial. In contrast, Tarnopolsky et algl concluded that a 6-mg/kg-' caffeine dose administered 60 minutes prior to exercise in six habitual (200 mg/dP1) caffeine consumers had no potential ergogenic effect. Caffeine administration incrt~asedplasma FFA levels prior to and during exercise, but did not change oxygen consumption, heart rate, respiratory exchange ratio (RER), Physical Therapy / Volume 75, Number rate of perceived exertion (RPE), or neuromuscular function (maximal voluntary strength, peak twitch torque, and motor unit activation). Plasma levels of glucose, epinephrine, and norepinephrine were also unchanged. Although blood levels of FFA were increased in the caffeine trial, an associated increase in FFA oxidation was not observed. A similar paradox was found in a study of five competitive cyclists who ingested a variety of potentially ergogenic substances in a crossover, single-blind protocol.% Caffeine given 60 minutes prior to exercise resulted in a reduction in muscle glycogen utilization when compared with the control trial. No difference, however, was noted in the RER between the caffeine and control trials, suggesting similar substrate utilization. These findings are similar to the results of a study of caffeine intake on performance in nine male marathoners, where an increase in plasma FFA was noted, with no change in RER." Titlow et a1102also found no ergogenic benefit from ingesting 200 mg of caffeine prior to a treadmill test in five male subjects. The authors found no difference in performance or substrate utilization. Information on the caffeine habits of subjects in these studies was not provided, and tolerance to the effects of caffeine may explain the results. Additionally, it has been suggested that RER may not accurately reflect substrate utilization after caffeine ingesti0n.9~ Side effects. Side effects of caffeine may include trembling and tremors, insomnia, nervousness, irritability, and anxiety. Caffeine also has a diuretic effect, which may result in fluid imbalance and inconvenience for the athlete. Regulation. Caffeine was considered a doping agent by the IOC until 1972, when caffeine was removed from the list of banned substances. This ruling was reconsidered, however, and in 1984 caffeine was again added to the list of doping agents. The illegal dosage is 12 mg/L of urine, and this dosage is equivalent to between 500 and 600 mg of caffeine in a 1- to 2-hour period.86 Caffeine is also banned by the NCAA at a urine level of 15 mg/L. Drug Testing Mandatory drug testing at international athletic events has been in existence at the Olympic Games since 1968. Comprehensive testing was not available until 1972, and testing for anabolic steroids was first initiated in 1976.2,103 The USOC and the NCAA have developed drug testing and drug education programs in attempts to ensure safe, fair competition. Mandatory drug testing programs were initiated in 1985 (USOC) and 1986 (NCAA) to eliminate the use of performance-enhancing and recreational drugs. Testing protocols, as well as analytical procedures for the most commonly used screening and confirmation tests, will be discussed. Currently, the USOC drug testing program applies to the US Olympic Festival, the Pan-American Games, the World University Games, and the Olympic Trials and Games. The USOC athletes are subject to testing at any time throughout the year, including the off season. Athletes may be tested while out of competition for the presence of anabolic-androgenic steroids, diuretics, and masking agents.lo4 Short-notice testing requires only 48 hours' advance notice via phone, personal contact, or return-receipt correspondence. Division I-A and I-AA football players and Division I men's and women's track athletes can be tested throughout the academic year for anabolic steroids and related masking agents. All other athletes are tested at championship events and bowl games. Under NCAA and USOC protocols, athletes may be chosen for testing in a variety of ways. For example, first-, second-, and third-place finishers in addition to a random sample from the remaining field may be chosen for testing.lo4Moreover, national governing bodies or NCAA schools may request or conduct their own drug testing programs.lo4 Although blood samples are currently under consideration for some drugs, such as EPO, urine is still the pre- ferred specimen for three reasons: (1) Most misused drugs are present in higher concentrations in the urine than in blood, (2) larger specimens are obtained in an easier fashion, and (3) urine sampling is a noninvasive process.lo4After selection for drug testing at an event, the athlete has 60 minutes in which to report, and a courier stays with the athlete during this time. After urine samples are collected under supervision at the drug testing station (at least 80 mL for KCAA athletes and at least 100 mL for USOC athletes), the urine is divided into two separate bottles. The urine in one bottle will undergo testing, and the other bottle is saved for use in the event of appeal. Drug analysis involves two phases: screening and confirmation. Screening allows for rapid testing of many samples and is designed to eliminate all negative samples from further testing. If a screening test is positive, illicit drug use is presumed only, and the sample undergoes confirmation. Screening tests are sensitive, but confirmatory tests are specific for drug detection. A positive sample is confirmed by a second test performed on urine taken from the same test bottle. Testing procedures most commonly used in screening include thin-layer chromatography (TLC), irnmunoassay (IA), gas chromatography (GC), and high-performance liquid chromatography (HPLC). Gas chromatography/ mass spectrometry (GC/MS) is most often used for confirmation, as it provides the most specific and definitive identification possible.104 Thin-Layer Chmmatography Thin-layer chromatography testing is based on the differences in the migration rate of various substances through a porous supporting medium.2 The degree of migration and the color are characteristic of certain drugs. Thinlayer chromatography can demonstrate the presence of a drug, but this procedure cannot speclfy the quantity of drug present.lo4This technique is both time consuming and nonspecific, and provides only a positive or negative response. Thin-layer chromatography is capable of detecting only a limited number of substances 12 to 24 hours after ingestion, resulting in a high number of false-negative results. lmmunoassay Imrnunoassays use antigen-antibody interactions to detect illegal substances. Antibodies that bind selectively to certain drugs or drug metabolites are chosen, and the sensitivity and the specdicity of this test are only as good as the antibody chosen2 The binding is proportional to the amount of drug in the urine and can be detected through enzymes, radioisotopes, or fluorescent compounds. With this technique, very small amounts of drug can be detected in a very small amount of urine, although this test may not differentiate between specific drugs within a class of drugs. Immunoassay has yielded false-positive results with some decongestants and nonsteroidal anti-inflammatory drugs.2 Radioimmunoassay (RIA) and fluorescence polarization immunoassay (FPIA) are specific IA techniques currently being used. Radioimmunoassay can detect some 17a-methyl, 17aethyl, and 1Pnortestosterone steroids despite its low ~pecificity.~O5 Immunoassay is both more sensitive and more specdic than TLC. Gas Chromatography Gas chromatography uses a separation technique to divide the urine extracts into the component parts. An inert gas carries the urine through chromatographic columns, and the samples are separated by their boiling temperature and by their affinity for the column. Compounds are identdied by separation time, called retention time.The retention time is unique and reproducible for each drug in a given chromatographic c01urnn.~High-performance liquid chromatography is similar to GC, except a liquid carries the sample through the chromotographic columns and the columns are not placed in a heated compartment. High-performance liquid chromatography is both sensitive and specdic, and it is simpler and faster than GC. Gas chromatography and HPLC are reliable methods for screening, and they allow for simultaneous determination of a wide variety of different compounds. High-performance liquid chromatography is used to screen for urinary caffeine levels and has been used to confirm the positive results obtained from other screening te~hniques.~ Some steroids can be analyzed with this technique, whereas HPLC and GC lack appropriate sensitivity to detect beta-adrenergic blo~kers.~O5J~~ Gas ChmmatographyIMass Spectrometry The most precise procedure for detection of banned substances is a combination of GC and MS.1°3J05 Gas chromatography/mass spectrometry is a two-step process, where GC separates the sample into its constituent parts, while MS provides the exact molecular identdication of the compounds. Compounds are separated by GC and are then introduced, one at a time, into a mass spectrometer. As the sample constituents enter the MS, they are bombarded by electrons, which cause the compound to break up into molecular fragments. The fragmentation pattern is reproducible and characteristic, and is considered the "molecularfingerprint" of a specdic compound. Gas chromatography/mass spectrometry is considered to be the most definitive method for confirming the presence of a drug in the urine and is approximately 100 to 1,000 times more sensitive than TLC.* Selective ion monitoring has been used to improve the GC/MS results.1°5 This procedure is the most costly, averaging approximately $200 per sample to test.2 Summary A variety of ergogenic aids are used by athletes attempting to gain an edge on a competitor. These aids fall into categories of nutritional, pharamcologic, physiologic, and psychologic. Some of these techniques have been shown to be efficacious when used in specific situations, whereas the benefit of others remains controversial. This controversy may be due to the ethical inability to test these substances in the same manner in which they are used. Moreover, blind testing is unable to be Physical Thera.py / Volume 75, Number 5 / May 1995 ~erformedin some situations (anasteroids) because of the psychoactive effects. Knowledge of these agents - and techniques is important to the physical therapist because patients may be using them recreationally or to performance and because the possibility of disease transmission. the . physical thera~istmay , play a in educating the or the public regarding ergogenic aids. Individuals may seek information after media pubabout ergogenic licity involving athletes and drugs. bolic oreo over. References 1 Voy R. Drugs, Sport, and Politics. Champaign, 111: Human Kinetics Inc; 1991:>11. 2 Wadler GI, Hainline B. Drugs and the Athlete. Philadelphia, Pa: FA Davis Co; 1989. 3 Strauss RH, Curry TJ. Magic, science and drugs. In: Strauss RH, ed. Drugs and Pegormance in Sports. Philadelphia, Pa: WB Saunders Co; 1987:>10. 4 Wagner JC. Enhancement of athletic performance with drugs: an overview. Sports Med. 1991;12:25(1-265. 5 Murray 'IH. The ethics of drugs in sport. In: Strauss RH,ed. Drugs and Petformance in Sports. Philadelphia, Pa: WB Saunders Co; 1987:ll-21. 6 Cowart VS. Drug testing programs face snags and legal challenges. The Physician and Sportsmedicine. 1988;16(2):165-173. 7 Haupt HA, Rovere GD. Anabolic steroids: a review of the literature. Am J Sports Med. 1984;12:4611-484. 8 Vaughan RD, Walter HJ, Gladis MM. Steroid use among adolescents: another look. AIDS. 1991;5(1):112-113. 9 DuRant KH, Rickert VI, Ashworth CS, et al. Use of multiple drugs among adolescents who use anabolic steroids. N Engl JMed. 1993;328: 922-926. 10 Landry GL, Primos WA. Anabolic steroid abuse. Adv Pediatr. 1990;37:185-205. 11 Fuentes RJ. Anabolic steroids and the athlete. I n Athletic Drug Reference 9 4 . Durham, NC: Clean Data Inc; 1%4:85-105. 12 Taggart HM, Bowden DA, Haffner S, et al. Reduction in high-density lipoproteins by anabolic steroid (Stanozolol) therapy for postmenopausal osteoporosis. Metabolism. 1982; 31:1147-1152. 13 Strauss RH. Anabolic steroids. In: Strauss RH,ed. Drugs and Pe$ormance in Sports. Philadelphia, Pa: WB Saunders Co; 1987:5967. 14 Council on Scientific Mairs. Medical and non-medic:al uses of anabolic-androgenic steroids. J u 4 . 1%0;264:292>2927. 15 Toohey JV. Trends in drug use behavior at ten Arizona high schools. Arizona Journal of Health, Ph,ysical Education and Recreation. Fall 1975:6-8. 16 Toohey JV. An analysis of drug use behavior at five American universities. J Sch Health. 1971;41:464-468. 17 Bucklev WE. Yesalis CE. Freidl KE. et al. Estimated ;revalence of anabolic sterdid use among male high school seniors. J m . 1988; 2603441-3445. 18 Windsor R, Dumitru D. Prevalence of anabolic steroid use by male and female adolescents. Med Sci sports here. 1989;21:494-497, 19 Terney R, McLain LG. The use of anabolic steroids in high school students. American Journal of Diseases in Childhood, 1990;144: %-103, 20 Gaa GL. Griffith EH, Cahill BR, et al. Prevalence of anabolic steroid use among Illinois high school students. Journal of Athletic Training. 1994;3:216-223. 21 Pope HG, Katz DL, Champoux R. Anabolic-androgenic steroid use among 1,010 college men. The Physician and Sportsmedicine. 1988;16(7):75-81. 22 Johnson MD, Jay MS, Shoup B, et al. Anabolic steroid use by male adolescents. Pediatrics. 1989; 85921-924. 23 National Collegiate Athletic Association. Steroid usage drops among student-athletes. NCRA News. September 1, 1993. 24 Kennedy MC. Anabolic steroid abuse and toxicology. Aust NZ JMed. 1992;22:374-381. 25 Wilson JD. Androgen abuse by athletes. Endocr Rev. 1988;9:181-199. 26 Kibble MW, Ross MB. Adverse effects of anabolic steroids on athletes. Clinical Pharmacy. 1987;6:686-692. 27 Haupt HA. Anabolic steroids and growth hormone. Am J Sports Med. 1993;21:468-474. 28 Burkett LN, Falduto MT. Steroid use by athletes in a metropolitan area. 7be Physician and Sportsmedicine. 1984;12(8):69-74. 29 Tingus SJ, Carlsen RC. Effect of continuous infusion of an anabolic steroid on murine skeletal muscle. Med Sci Sports Ezerc. 1993;25: 485-494. 30 Crist DM, Stackpole PJ, Peake GT. Effects of androgenic-anabolic steroids on neuromuscular power and body composition. J Appl Physiol. 1983;54:366-370. 31 Elashoff JD, Jacknow AD, Shain SG, et al. Effects of anabolic-androgenic steroids on muscular strength. Ann Intern Med. 1991;115: 387-393. 32 Lamb DR. Anabolic steroids in athletics: How well do they work and how dangerous are they? Am J Sports Med. 1984;12:31-38. 33 Hervey GR, Knibbs AV, Burkinshaw L, et al. Effects of methandienone o n the performance and body composition of men undergoing athletic training. Clin Sci. 1981;60:457461. 34 McNutt RA, Ferenchick GS, Kirlin PC, Hamlin NJ. 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