Ergogenic Aids

In the context of sport, an elgogenic aid can be broadly dejined as a technique Lori A Thein
or substance used for the purpose of enhancing performance. Ergogenic a i d Jill M Thein
have been classzj?ed as nutritional, pharmacologic, physiologic, or psychologic Gregory L Landry
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 ergo-
genic 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

Key Words: Ergogenic aids, Pharmacology, Sports medicine, Sports physical therapy,
stmids.

Many athletes have turned to ergo- decades are the pharmacologic and In the 19th century, the French con-
genic aids in hopes of achieving an physiologic aids. Anabolic-androgenic cocted uin mariani, a drink mixture of
edge on their opponents. The term steroids, blood doping, erythropoietin, coca leaves and wine, which report-
"ergogenic" means "tending to in- human growth hormone, clenbuterol, edly reduced fatigue and hunger sen-
crease work" and, in the context of and caffeine are some of the ergogenic sation during prolonged a~tivity.3,~
In
sport, includes techniques used to aids currently used by athletes at- the late 1800s, marathon runners fre-
increase energy production and per- tempting to achieve superior quently drank alcohol during races.
formance. Nutritional and psychologic performance. Brandy, champagne, and another
ergogenic aids continue to be used then-popular "stimulant,"strychnine,
regularly and safely. The use of carbo- Attempts to gain competitive advan- were used by American athletes.3
hydrate loading, vitamins, electrolyte tages over competitors is not a new
solutions, ritual preparation proce- phenomenon. The term "doping" has In the 20th century, the use of stimu-
dures, visualization, and stress man- roots in a South African dialect when lants in the 1952 Olympic Winter
agement techniques receives little it referred to a liquor stimulant used in Games, followed by suspicion of ana-
attention in the popular press, but religious ~eremonies.~ Herbs and bolic steroid use by the soviet athletes
these can be considered ergogenic mushrooms were consumed by an- in 1954, focused attention on the use
aids. The ergogenic aids receiving the cient Greek Olympic athletes in at- of ergogenic aids.*The 1960s saw a
greatest attention in the last several tempts to improve their perf~rrnance.~ dramatic increase in drug abuse, with
amphetamines implicated in the
deaths of several cyclists.' The appar-
ent widespread use of anabolic ste-
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,
roids at the 1964 Olympics was severe
Madison, Wl 53705 (USA). Address all correspondence to Ms Thein. enough to warrant drug testing at the
1968 Olympic Games.5 Improvements
JM Thein, PT, ATC, is Physical Therapist, Outpatient Orthopedics, University of Wisconsin Hospi-
tal, 600 Highland Ave, Madison, WI 53792. in detection using mass spectrometry
and gas chromatography resulted in
GL Landry, MD, is Assistant Professor, Department of Pediatrics, Head, Section of Sports Medicine, the disqualification of 19 athletes from
and Head Medical Team Physician, University of Wisconsin Medical School, 600 Highland Ave,
Madison, W 53792. the Pan-American Games in 1983, and

Physical Therapy / Volume 75, Number 5 / May 1995 426 / 95

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 in the surrender of a silver medal by
Martti Vainio (1984 Olympic Games)
and a gold medal by Canadian Ben
Johnson (1988 Olympic game^).^,^^^
Use of ergogenic aids by patients
being treated by physical therapists
might affect the patients' response to
treatment. Side effects of some ergo-
genic aids can affect heart rate, blood
pressure, or other physiologic mea-
sures. Individuals using injectable
drugs are at risk for disease transmis-
sion from shared needle~.~.9 Adoles-
cents 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.
"Ergogenic aids" is a broad category of
topics (including physiologic, phanna-
cologic, psychologic, and nutritional'),
and the choice of substances used as
ergogenic aids changes with improve-
ments in technology and detection
procedures. The list of techniques and
substances used as ergogenic aids is
too extensive for a complete discus-
sion within this article The purposes
of this article are to present several
commonly abused agents and tech-
niques, to examine their potential risks
and benefits, and to discuss drug
testing procedures.
Phannacologic Ergogenic Aids
Anabolic-Androgenic Steroids
Anabolic steroids are synthetic deriva-
tives of the male hormone testoster-
one. These androgens are prescription
drugs that have legitimate, therapeutic
uses. They are prescribed for children
and adolescents to treat delayed pu-
berty, aplastic anemia, and hypogo-
nadism.l0>" In the adult population,
steroids are used successfully to treat
certain types of anemias, hereditary
angioedema, some gynecologic condi-
tions, protein anabolism, and male
hypogonadism. Additionally, they may
have a role in the treatment of osteo-
p0rosis.~~J3 Medical indications ac-
count for fewer than 3 million pre-
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scriptions of anabolic steroids annually
in the United States.14Illicit use, how-
ever, results in a much larger and
untold number of annual usages.
Physical therapists may treat individu-
als who use anabolic steroids. Al-
though 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 long-
term deleterious effects of anabolic
steroid use.
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 ana-
bolic 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 Ari-
zona high-school male athletes15 and
15% of Arizona State University ath-
letes used anabolic steroids.16Data
have demonstrated that anabolic ste-
roids are becoming increasingly popu-
lar among high-school athletes and
nonathlete~.l5.~7-~0In a 1988 nation-
wide 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 non-
athletes. 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 respon-
dents, 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-
Physical Tht:rapy / Volume 75, Number 5 /May 1995
r o i d ~Of
. ~the
~ 1,881 Georgia high-
school 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 high-
school 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 individu-
als using steroids, 64% were athletes,
26% reported using a stacking tech-
nique, and 21% listed a teacher/coach
as the main source who got them
interested in using steroids. Twenty-
one 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 Asso-
ciation (NCAA) has been collecting
data on the use of anabolic steroids in
collegiate athletes since 1985. Anabolic
steroid use among male football play-
ers 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 com-
monly used anabolic steroids, see
Table 1.
Pharmacology and physiologic
effects. All anabolic steroids are deriv-
atives of the male sex hormone testos-
terone. 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 an-
drogenic effects are inseparable. When
the hormone binds with receptors in
various tissues, the same type of re-
ceptors produce anabolic and andro-
genic 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 appropri-
ate name for these compounds is
"anabolic-androgenic steroids," but the
term is frequently shortened to "ana-
bolic steroids." Attempts to enhance
the anabolic effects while diminishing
the androgenic effects have brought
about the creation of over 40 chemical

Table 1. Commonly Used Anabolic ~ t e r o i d s " ' ~ ~ ~ ~
Generic Name Brand Name
--
Oral
Ethylestrenol Maxibolin
Fluoxymesterone Halotestin
Methandrostenolone Dianabol
Methyltestosterone Metadren, Oreton Methyl
Oxymetholone Anadrol-50
Stanozolol Winstrol
Injectable
Nandrolone Deca-Durabolin
Nandrolone phenor~ouibate Durabolin
Testosterone cypionate Depo-testosterone
Testosterone propionate Oreton
Testosterone enanthate Delatestryl
modifications of the core ster0id.l
When taken orally or parenterally in
its origins[ state, testosterone is quickly
degraded by the liver, and blood lev-
els necessary to achieve anabolic
effects are not sustained. Conse-
quently, three modifications of the
testosterone molecule have been
made (designated as types A, B, and
C ) and demonstrate increased effec-
t 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 prepara-
tions 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 mecha-
n i s m ~Many
. ~ ~ cells in the body, in-
cluding skeletal muscle, possess recep-
tors that bind testosterone or similar
hormones. A steroid-receptor complex
is formed. causing synthesis of en-
zymes, 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,
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Derivative
19-Nortestosteroneester
19-Nortestosterone
Testosterone ester
Testosterone ester
Testosterone ester
and ~trength.7JOJ~-~~ Anabolic steroids
may also enhance lean body mass via
an anticatabolic effect.27During epi-
sodes of stress, such as intense exer-
cise, 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 nitro-
gen 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 mecha-
nisms. 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 ag-
gressiveness, 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 ab-
sorbed from the stomach, excreted
fairly rapidly from the body due to
their short half-lives, more toxic than
injectable steroids to the liver, and
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 In-
jectable 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 inject-
able 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 taper-
ing 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 "cy-
cling."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 muscu-
lar strength provide inconsistent re-
sults. 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 ste-
roid portion of the study. Moreover,
the doses that can be ethically a h -
istered are well below those that ath-
letes report using.
 After reviewing and statistically analyz-
ing 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 ath-
lete 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. Addition-
ally, Crist et also found no improve-
ment in isokinetic power measure-
ments 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 rea-
sons: (1) There was no placebo group,
(2) there was a failure to randomize
subjects into groups, (3) strength mea-
surements were not objective, or (4)
the percentage change in strength
could not be ascertained. Of the re-
maining 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 dBer-
ence of 5%. No evidence existed to
support enhanced muscle strength in
untrained individuals.
Weight gain is commonly associated
with anabolic steroid use and has
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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 place-
bo.32833 Whether these gains reflect
muscle mass increases or fluid reten-
tion remains unclear. Although radio-
graphic studies and body-density mea-
surements indicate increases in muscle
size and lean body mass, the concur-
rent increase in total body potassium
and nitrogen are disproportionate to
the weight gain." Therefore, it is un-
clear 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 ste-
r 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 left-
hemispheric 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 re-
tired NFL star, is speaking publically
about steroid abuse, which caused his
cardiomyopathy.ll More common
adverse effects involve the hepatic,
endocrine, musculoskeletal, cardiovas-
cular, 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 revers-
ible upon discontinuation of the
druge26Oral anabolic steroids may
cause cholestasis, jaundice, and, sel-
dornly, a pathologic condition associ-
ated exclusively with oral anabolic
steroids, peliosis hepatis. Pelosis hepa-
tis 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
Physical Therapy / Volume 75, Number 5 / May 1995
anabolic steroids. Two cases of hepa-
tocellular carcinoma have been re-
ported 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 ste-
r0id.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 hypo-
thalamus. Exogenous anabolic steroid
replaces testosterone in the negative
feedback system at the level of the
pituitary and hypothalamus, resulting
in a decreased production of gonado-
tropins. Reduction in serum concentra-
tions of pituitary interstitial cell-
stimulating hormone (ICSH) and
follicle-stimulating hormone (FSH)
causes a decrease in testosterone pro-
duction from the te~tes.lO~~6,~Z
Physical changes associated with ana-
bolic 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 discon-
tinuing the drug, yet male infertility
has been reported up to 7 months
after cessation of steroid use.1° Gy-
necomastia is a well-known side effect
of anabolic steroids and is character-
ized by a subareolar, bunonlike unilat-
eral or bilateral plaque of ti~sue.~3
Gynecomastia is caused by the estro-
gens estradiol and estrone, which are
produced when androgens are con-
verted in extraglandular tissue. Estra-
diol levels in athletes who are stacking
steroids can be seven times the nor-
mal level of ovulating women.lO At-
tempts to use estrogen inhibitors, such
as human chorionic gonadotropin or
tarnoxifen, have proven to be unsuc-
cessful. In extreme cases, the develop-
ment of breast tissue is not totally
reversible, and mastectomy may be
required.43
 Evidence of increased musculotendi-
nous 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, ana-
bolic steroids cause premature closure
of the epiphyses, resulting in de-
creased adult height.11
Use of anabolic steroids has been
linked to alterations in lipid pro-
fiIes.l2J4,26,*5The most consistent side
effects of anabolic steroid use are a
significant rise in total serum choles-
terol level and a decrease in high-
density lipoprotein (HDL). Reduced
HDL levels are such a consistent find-
ing 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 low-
density lipoproteins (LDL) and a trip-
ling 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. Dur-
ing the time these athletes did not use
drugs, they had high HDL levels and
relatively low LDL levels. This obser-
vation 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 con-
centrations in athletes using anabolic
steroids when compared with un-
trained 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
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main effects of androgens on lipopro-
teins are the consequence of an inhi-
bition 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, aggressive-
ness, irritability, nervous tension,
changes in libido, mania, and psycho-
sis. Up to 80% of steroid users are
aware of overly aggressive and violent
behavior during periods of high con-
sumption 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 build-
ers, 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 symp-
toms with anabolic steroid use. Delu-
sions, hallucinations, anorexia, hyper-
activity, 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 consis-
tently used anabolic steroids. The
women used stacking and cycling
techniques, taking up to nine times
the manufacturers' recommended
dosages. Perceived side effects in-
cluded lower voice, enlarged clitoris,
increased libido, oligomenorrhea or
amenorrhea, increased aggressiveness,
acne, increased growth of body hair,
and decreased body fat. Side effects
such as enlarged clitoris and deepen-
ing 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 am-
bolic steroid transactions illegal and
subject to felony charges.14Anabolic-
androgenic 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 ante-
rior 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 defi-
cient. Additionally, GH is being stud-
ied 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 ado-
lescents and women.'j Serum levels
vary throughout the day owing to its
intermittent, pulsatile release, but aver-
age 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-inhibitinghor-
mone (SRIH). Growth hormone re-
lease can be affected by multiple fac-
tors, including sleep, exercise, stress,
hypoglycemia, alpha-adrenergic ago-
nists, beta-adrenergic antagonists, GH
levels, and dopaminergic agonists
(Tab. 2).2.i2-55Growth hormone in-
creases in response to hypoglycemia
and exercise, and the largest GH surge

Table 2. Factors Affecting Growth Hormone Secretiona
Stimulative
Physiologic
Sleep
Exercise
Stress (physical or psychological)
Postprandial hyperarninoacidemia
Postprandial hypoglycemia (relative)
Pharmacologic
Hypoglycemia:
Absolute: insulin or 2-deoxyglucose
Relative: postglucagon
Hormones:
Peptides (GRH, ACTH, a-MSH, vasopressin)
Estrogen
Neurotransmitters:
a-Adrenergic agonists (clonidine)
p-Adrenergic antagonists (propranolol)
Serotonin precursors (5-hydroxytryptaine)
Dopaminergic agonists (L-dopa, apomorphine,
bromocritine)
GABA agonists (muscirnol)
Pathologic
Protein depletion and starvation
Anorexia nervosa
Chronic renal failure
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: McGraw-
Hill 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 nega-
tive 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 endog-
enously released GH.'
The primary function of GH is to
promote growth via the generation of
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Suppressiveb
Postprandial hyperglycemia
Elevated free fatty acids
Hormones:
Somatostatin
Sornatomedin C (IGF-1)
Growth hormone
Progesterone
Neurotransmitters:
a-Adrenergic antagonists (phentolamine)
P-Adrenergic agonists (isoproterenol)
Serotonergic antagonists (methysergide)
Dopaminergic antagonists
(phenothiazines)
Cholinergic (muscarinic)antagonists
(pirenzepine)
Obesity
Hypothyroidism and hyperthyroidism
Acromegaly: dopaminergic agonists
somatomedins, spechcally insulinlike
growth factor (IGF-1). Growth hor-
mone 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 synthe-
sis by the cells, with concurrent reduc-
tion of protein catabolism.56 The GH-
mediated growth is dfierent from the
growth that occurs as a result of work.
New RNA must be synthesized for
exercise-induced muscle growth,
Physical The]rapy / Volume 75, Number 5 / May 1995
whereas GH-mediated growth occurs
as a result of increases in the rate and
translation of existing RNA.52,54
Growth hormone has potent effects on
carbohydrate and lipid metabolism,
Functioning to decrease glucose and
protein metabolism by shifting oxida-
tive 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 de-
crease fat and increase lean body
ma~s.5~
Administration. Therapeutic dosages
of GH for individuals with GH defi-
ciency range from 0.06 mg/kg to 0.1
mg/kg three times weekly, depending
on the spechc medication2 Recombi-
nant human growth hormone (rGH) is
currently used because of cases in
which Creutzfeldt-Jakob disease was
spread via use of the naturally occur-
ring hormone.57 Two forms of rGH
are currently available, one containing
the entire natural sequence and a
second containing an additional me-
thionyl 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, vaso-
pressin, 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, lead-
ing to the anecdotal reports of in-
creases in muscle bulk and ~trength.5~
Ergogenic efficacy. The observed
muscle size increase without simulta-
neous strength increase in individuals
with acromegaly prompted the study
of the effects of a concurrently admin-
istered GH and resistive exercise pro-
gram. Yarasheski et a15"valuated the
effectiveness of exogenously adminis-
tered GH on muscle growth in a
 group of 16 untrained male subjects.
After 12 weeks of training in combina-
tion with 5-d/wk GH injections, the
treatment group demonstrated protein
balance when compared with a pla-
cebo group. Quadriceps femoris mus-
cle protein synthesis rate, torso and
limb circumferences, and muscle
strength, however, were not increased.
The authors concluded that the in-
crease in fiat-free mass (FFM) was due
to increases in lean tissue other than
skeletal muscle, but they d ~ d not spec-
tulate 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 exer-
cise 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 adrninistra-
tion of GH in rats. Neither improved
tension development nor enhanced
performance, however, were found
in the nonnal or hypertrophied
muscle^.^^^^^
Side effects. Adverse effects of large
quantities of GH in adults include
acromegaly with associated myopathy,
peripheral neuropathy, glucose intoler-
ance, increased plasma cholesterol
and triglyceride concentrations, coro-
nary artev disease, and cardiomyopa-
thy.2,27,52,54
In prepubescent athletes,
excessive quantities of GH result in
gigantism. The musculoskeletal and
cardiac effects associated with exces-
sive GH use may be irreversible, even
after discontinuation of the hormone.
Moreover, needle sharing for intramus-
cular administration carries the risk of
disease transmission.
Regulation. Human GH, synthetic
GH, and GH-releasing factors are all
Physical Therapy /Volume 75, Number 5 /May 1995
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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 medi-
cal tests exist for the detection of hu-
man GH.
Clenbuterol
Clenbuterol is a beta2-adrenergic ago-
nist that has proposed ergogenic prop-
erties resulting from central nervous
system (CNS) stimulation. It is a sym-
pathomimetic drug that has a periph-
eral excitatory action on smooth mus-
cle, 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
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
Increasedthermogenic effect
Decreased appetite
"Mects brown (fat) cells
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 de-
creasing 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 beta-
agonist treatment.63a65
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 mem-
branes 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 alert-
ness, and decreased appetite.(*l
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 endur-
ance. Increased glycogenolysis from
the liver may increase carbohydrate
availability, and increased skeletal
muscle blood flow may enhance the
peripheral delivery system.
Protein anabolism is a consistent find-
ing 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, con-
tractile activity) mechanisms may par-
ticipate in the hypertrophy process65
Administration. Clenbuterol hydro-
chloride 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 maxi-
mum growth within 8 days65 Attenua-
tion takes place after approximately 14
days, likely due to beta-receptor satu-
ration and subsequent receptor down
regulation. Rothwell et a169 demon-
strated a 50% reduction in muscle
beta-receptor density after 18 days of
chronic clenbuterol treatment in rats.
Intermittent administration of beta-
agonists 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, al-
though, as with many ergogenic aids,
anecdotal reports exist. Anecdotal
reports suggest that athletes often
combine clenbuterol with other hor-
mones such as anabolic steroids or
GH to exponentially increase its ef-
fects, a practice that is supported by
animal research.6"
Ergogenic efficacy. Most studies of
ergogenic efficacy have been per-
formed 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
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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 ap-
pears to promote fiber-specific (fast-
twitch glycolytic) muscular hypertro-
phy, with increases in the cross-
sectional 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 glyco-
lytic, and slow oxidative fibers. Muscle
RNA was increased consistent with the
increase in muscle protein, and clen-
buterol appeared to enhance protein
anabolic effects via a depression of
protein degradation rates, with little or
no change in protein synthesis. Al-
though other researchers have found
similar anabolic changes, these effects
were the result of increases in protein
synthesis71 or increases in both synthe-
sis 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, salbu-
tamol, 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 adminis-
tration of an oral form of sustained-
release salbutarnol. The treatment
group demonstrated increases in
quadriceps femoris and hamstring
muscle group strength compared with
the control group. The single-dose and
Physical The:rapy / Volume 75, Number 5 / May 1995
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 ad-
ministration can affect results.
Side effects. Side effects of clen-
buterol use are slmilar to those of any
beta,-agonist. Tremor, tachycardia,
anxiety, palpitations, headache, nau-
sea, anorexia, and insomnia are com-
mon complaints. Additionally, poten-
tially serious side effects include
cardiac muscle hypertrophy and dys-
rhythrnia, 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 beta-
agonists are widely used. Urine levels
of 0.5 ng/mL are detectable by gas
chromatography and mass spectrome-
try 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) pro-
duction. 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 liv-
e ~ - 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 bio-
chemically and immunologically, al-
though some minor differences exist.
Commercial production utilizes recom-
binant 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 ben-
efit from the use of rEP0.76,77
Pharmacology and physiologic
effects. Erythropoietin and rEPO are
used specifically by endurance athletes
 to increase aerobic endurance, with
effects similar to that of blood doping.
Erythropoietin is a major factor in the
stimulation, proliferation, and matura-
tion of the bone marrow stem cell,
which, in turn, increases the rate of
@-@-@ * 2s

vI
RBC pr0duction.~5Hypoxia, with a
subsequent decrease in renal blood
flow, or low levels of circulating he- Stem BFU-E
moglobin stimulate the production cell
and secretion of EPO by these sites. In
normal bone marrow, stem cells differ-
entiate into late burst erythroid colony
forming units (BFU-E), which replicate
and differentiate into early erythroid
colony forming unit cells (CFU-E) and
@
cr '.I\::
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).
0
Administration. Administration of
rEPO in patients with end-stage renal
disease is recommended at a level of
I
150 U/kg three times per week with
adjustmen& as necessary to achieve a
response.7s The half-life of rEPO ad-
n
I
ministered intravenously is approxi-
mately 5 to 11 hours, whereas the
half-life is 25 hours when administered
subcutaneously, depending on dos-
age. Absorption is slower with subcu-
taneous administration, with peak
concentrations occurring 10 to 15
hours after administration.7679 Mature RBC

Ergogenic efficacy. The proposed
ergogenic benefits of EPO are derived
from the early release of marrow re-
ticulocytes (young RBCs), stimulation
of megakarocytopoesis (platelet pre-
cursors), increased hemoglobin syn-
thesis by KBC precursors, proliferation
of BFU-E, and proliferation and dfier-
entiation of CFU-E cells. The resultant
increase in RBCs will increase oxygen
carrying capacity, thereby increasing
oxygen availability to the tissues. In-
creased oxygen availability to the
tissues al1c)ws for increased adenosine
triphosphate (ATP) production and
improved aerobic performance. Pa-
tients receiving 600 U/kg of body
Figure. stimulation of red blood cell production by erytbropoeitin. BFU-E= burst-
forming 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: Molecular-
toClinical. St Louis, Mo: Mosby-Year Book lnc; 1991:860.)
weight intravenously twice weekly for Side effects. Adverse effects of EPO
21 days demonstrated a 41% greater or rEPO are due to the increase in
RBC volume than did those receiving RBC production and are dose-
a p l a c e b ~Ekblom
.~ and BerglundB1 dependent. Hypertension and hyper-
administered rEPO to 15 well-trained viscosity (hematocrit over 55%) of the
male subjects at a dosage of 50 U/kg blood are two potentially life-
subcutaneously three times per week threatening adverse effects. Athletes
for 6 weeks. Results demonstrated are particularly susceptible to the
increased hematocrit of lO?h, exercise effects of hyperviscosity due to the
time to exhaustion by 17%, maximal unpredictable clearance of rEPO from
oxygen consumption by 8%, and the serum and the biological effects
systolic blood pressure by 8%. that last for the life of the RBC (up to

Physical Therapy / Volume 75, Number 5 / May 1995 434 / 103

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 120 days). Effects may be exacerbated
during prolonged endurance events
when dehydration increases the hy-
perviscosity. Symptoms of hypervis-
cosity include headache, dizziness,
vertigo, tinnitus, visual changes, an-
gina, exercise-induced claudication,
encephalopathy, and s e i ~ u r e sThe
.~
athlete may also experience a throm-
boembolic hypoxic event because of
"sludging" of the blood. Several Euro-
pean 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
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 diffi-
cult. Recombinant EPO is slightly
different from EPO, and advances in
technology may detect these ditfer-
ences. Assessment of the RBC age
may be beneficial, as athletes abusing
EPO should demonstrate a younger
RBC population. Although the esti-
mated yearly cost of legitimately ob-
tained EPO of $5,000 to $6,000 may
impede its use by some athletes, no
definitive deterrents exist.83
Caffeine
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 pharmaceuti-
cals.% Consequently, caffeine consum-
ers 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
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caffeine. Analgesics and cold prepara-
tions contain approximately 30 to 65
mg of caffeine.84The physical therapist
must be aware of the action and ef-
fects of caffeine because of its wide-
spread use and its sympathetic and
diuretic side effects.
Pharmacology and physiologic
effects. Caffeine (1,3,7-trimethyl-
xanthine) is one of three xanthine
derivatives producing similar physio-
logical responses.84-%,8'The other two
derivatives, theobromine and theo-
phylline, are found in cocoa and tea,
respectively. Of the three xanthine
derivatives, caffeine produces the most
CNS activity and theobromine pro-
duces 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. Caf-
feine 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 asymp-
tomatic adults, with an average half-
life 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 proposed to exert its effects
by (1) antagonism of adenosine recep-
tors:* (2) inhibition of enzyme activity
such as phosphodiesterase,75 (3) alter-
ing the release or uptake of calcium
from the sarcoplasmic r e t i c u l ~ m , ~ 5 > ~ ~tional status, and inconsistency in the
(4) altering the calcium permeability of
the sarcolemma, or (5) facilitating
neuromuscular impulse transmi~sion.~~ ance to many of the effects of caffeine
Caffeine acts as a CNS stimulant, in-
creasing arousal, reducing fatigue,
decreasing motor reaction time, and
changing normal electroencephalo-
gram recordings. Excessive caffeine
usage can produce irritability, restless-
ness, diarrhea, insomnia, and anxiety.
Inhibition of phosphodiesterase results
in elevated levels of CAMP, an impor-
tant regulator of cellular functions.
Maintenance of elevated CAMP levels
Physical Th~erapy/ Volume 75, Number 5 /May 1995
results in increased neurotransmitter
release and neuronal activation, regu-
lation of hormone-induced glycogen-
olysis and lipolysis, and dose-specfic
CNS s t i m u l a t i ~ nCentral
. ~ ~ ~ ~nervous
system arousal is also facilitated di-
rectly by caffeine's inhibition of adeno-
sine receptors in the brain. Adenosine
acts as a CNS depressant, hypnotic,
and anticonvulsant, and caffeine's
blocking of adenosine receptors in-
creases neurotransmitter release and
lowers the threshold for neuronal
activati0n.~5In the athlete, the CNS
stimulation may increase mental alert-
ness and reduce fatigue.
In addition to decreasing the percep-
tion of fatigue, athletes use caffeine as
an ergogenic aid because of its pro-
posed ability to increase circulating
levels of FFA and to "spare" glycogen
by altering substrate utilization. Caf-
feine 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 intracel-
lular CAMP,which accelerates hydroly-
sis of stored triglycerides, or to direct
xanthine inhibition of phosphodiester-
ase.8' The caffeine-facilitated increases
in blood EFA levels are suggested
to produce shifts in substrate utiliza-
tion, increasing FFA oxidation and
slowing glycolysis, thereby "sparing"
glyc0gen.~99%
Ergogenic efficacy. Studies examin-
ing the glycogen sparing effect of
caffeine have provided mixed results.
Dserences in the quantity and timing
of caffeine administration, variations in
exercise protocols and subject nutri-
caffeine "naivet~"of the subjects have
likely produced this disparity. Toler-
develops within a few days, and the
results of caffeine ingestion on perfor-
mance are highly dependent on an
individual's normal quantity and
schedule of caffeine c o n ~ u m p t i o n . ~
Habitual caffeine consumption can
attenuate heart rate and blood pres-
sure, and catecholaminergic responses
to acute caffeine administration can
occur within a few days.91 Fisher et
aP2 found that habitual caffeine users
 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 re-
sulted 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,
several researchers93~95~97,~ have found
increased blood lactate levels follow-
ing caffeine ingestion and exercise.
Ravussin et a199 observed a higher rate
of fat oxidation and decreased carbo-
hydrate 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 caffeine-
naive 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 con-
sumed 10 mg/kg-' of caffeine imme-
diately before a treadmill run to ex-
haustion.lol The athletes ran farther
during the caffeine trial, and they had
increased blood lactate and blood
glucose responses at the end of exer-
cise during the caffeine trial.
In contrast, Tarnopolsky et algl con-
cluded that a 6-mg/kg-' caffeine dose
administered 60 minutes prior to exer-
cise in six habitual (200 mg/dP1) caf-
feine consumers had no potential
ergogenic effect. Caffeine administra-
tion 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
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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 asso-
ciated 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 ergo-
genic 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 perfor-
mance in nine male marathoners,
where an increase in plasma FFA was
noted, with no change in RER." Tit-
low et a1102also found no ergogenic
benefit from ingesting 200 mg of caf-
feine 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 sug-
gested that RER may not accurately
reflect substrate utilization after caf-
feine 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 imbal-
ance 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 dos-
age is 12 mg/L of urine, and this dos-
age 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. Com-
prehensive testing was not available
until 1972, and testing for anabolic
steroids was first initiated in 1976.2,103
The USOC and the NCAA have devel-
oped drug testing and drug education
programs in attempts to ensure safe,
fair competition. Mandatory drug test-
ing 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 pro-
gram applies to the US Olympic Festi-
val, 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 pres-
ence 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 mask-
ing agents. All other athletes are tested
at championship events and bowl
games. Under NCAA and USOC proto-
cols, athletes may be chosen for test-
ing 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 govern-
ing 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 pro-
cess.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 sam-
ples 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 con-
firmatory tests are specific for drug
detection. A positive sample is con-
firmed 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 chromatogra-
phy (HPLC). Gas chromatography/
mass spectrometry (GC/MS) is most
often used for confirmation, as it pro-
vides the most specific and definitive
identification possible.104
Thin-Layer Chmmatography
Thin-layer chromatography testing is
based on the differences in the migra-
tion rate of various substances through
a porous supporting medium.2 The
degree of migration and the color are
characteristic of certain drugs. Thin-
layer chromatography can demon-
strate 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 nega-
tive response. Thin-layer chromatogra-
phy is capable of detecting only a
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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 sub-
stances. Antibodies that bind selec-
tively to certain drugs or drug metabo-
lites 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 de-
tected through enzymes, radioiso-
topes, 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. Immu-
noassay has yielded false-positive
results with some decongestants and
nonsteroidal anti-inflammatory drugs.2
Radioimmunoassay (RIA) and fluores-
cence polarization immunoassay
(FPIA) are specific IA techniques cur-
rently being used. Radioimmunoassay
can detect some 17a-methyl, 17a-
ethyl, and 1Pnortestosterone steroids
despite its low ~pecificity.~O5 Immuno-
assay 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 chromato-
graphic columns, and the samples are
separated by their boiling temperature
and by their affinity for the column.
Compounds are identdied by separa-
tion time, called retention time.The
retention time is unique and reproduc-
ible for each drug in a given chroma-
tographic c01urnn.~High-performance
liquid chromatography is similar to
GC, except a liquid carries the sam-
ple through the chromotographic
columns and the columns are not
placed in a heated compartment.
High-performance liquid chromatogra-
phy 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
Physical Thera.py / Volume 75, Number 5 / May 1995
for simultaneous determination of a
wide variety of different compounds.
High-performance liquid chromatogra-
phy is used to screen for urinary caf-
feine 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 detec-
tion of banned substances is a combi-
nation of GC and MS.1°3J05 Gas chro-
matography/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. Com-
pounds 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 mo-
lecular fragments. The fragmentation
pattern is reproducible and character-
istic, and is considered the "molecular-
fingerprint" of a specdic compound.
Gas chromatography/mass spectrome-
try is considered to be the most defini-
tive method for confirming the pres-
ence of a drug in the urine and is
approximately 100 to 1,000 times more
sensitive than TLC.* Selective ion mon-
itoring has been used to improve the
GC/MS results.1°5 This procedure is
the most costly, averaging approxi-
mately $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, pharamco-
logic, 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
 ~erformedin some situations (ana-
bolic steroids) because of the psycho-
active effects. Knowledge of these
- and techniques is important to
agents
the physical therapist because patients
may be using them recreationally or to
performance and because
the possibility of disease transmission.
oreo over. the .physical
, thera~istmay
play a in educating the
or the public regarding ergogenic aids.
Individuals may seek information
about ergogenic after media pub-
licity involving athletes and drugs.
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