pharmacology

An Independent Study Course Designed

for Individual Continuing Education

Ergogenic Substances

Independent
Study Course 16.1.5

Peter A. Huijbregts, PT, MSc, MHSc, DPT,

OCS, MTC, CSCS, FAAOMPT, FCAMT
University of St Augustine for Health Sciences
St Augustine, Florida
The Journal of Manual and Manipulative Therapy
Forest Grove, Oregon
Shelbourne Physiotherapy Clinic
Victoria, British Columbia
Dynamic Physical Therapy
Cadillac, Michigan

Ellen Pong, BA, MOT, DPT

University of St Augustine for Health Sciences
St Augustine, Florida
NovaCare Rehabilitation
Milton, Florida
 Pharmacology
Mary Ann Wilmarth, PT, DPT, MS, OCS, MTC, Cert MDT—Editor

May 2006

Dear Colleague,

I am pleased to welcome you to Ergogenic Substances by Peter A. Huijbregts, PT, MSc, MHSc, DPT,
OCS, MTC, CSCS, FAAOMPT, FCAMT and Ellen Pong, BA, MOT, DPT. This is the fifth monograph
in the Orthopaedic Section Independent Study Course series 16.1, entitled Pharmacology.

Dr Peter Huijbregts received his diploma in physical therapy from Hogeschool Eindhoven in The
Netherlands, his master of science in manual therapy from Vrije Universiteit Brussel in Belgium, his
master of health science in physical therapy from the University of Indianapolis, and his doctor of
physical therapy from the University of St Augustine for Health Sciences. He is a physiotherapy con-
sultant for Shelbourne Physiotherapy in Victoria, British Columbia, an educational consultant for
Dynamic Physical Therapy in Cadillac, Michigan, as well as an assistant professor of online education
for the University of St Augustine. In addition, Dr Huijbregts is the editor-in-chief for the Journal of
Manual and Manipulative Therapy, holds numerous certifications, and has published extensively.

Dr Ellen Pong received her master’s in occupational therapy as well as her doctor of physical ther-
apy from the University of St Augustine for Health Sciences. In addition, she has a bachelor of arts
in journalism and English from Louisiana College. Dr Pong is an online instructor of pharmacolo-
gy for the University of St Augustine, and is a staff physical and occupational therapist for Novacare
in Milton, Florida. Her clinical experience is extensive and covers literally all areas of the body. We
are very pleased to have the expertise from both Dr Huijbregts and Dr Pong for this monograph.

This monograph describes the mechanism of action, effects on performance, medical indications,
side effects, and testing and regulation for the following: anabolic-androgenic steroids, androstene-
dione, human growth hormone, creatine, beta-hydroxy-beta-methylbutyrate, alcohol, caffeine,
amphetamines, and erythropoietin. The information is very straightforward and the case studies give
a good indication of how this can be applied in the clinic. The authors touch on the ethical and
legal implications for the physical therapist when dealing with clients and any of the above-men-
tioned ergogenic substances. This is not always a clear situation for physical therapists, but it is
something that needs to be addressed.

I believe that the detailed information in this monograph will give the reader greater insight into the
complexity of ergogenic substances and the delicate balance that is necessary when dealing with
clients and this pharmacological topic.

Best regards,

Mary Ann Wilmarth, PT, DPT, MS, OCS, MTC, Cert MDT
Editor

2920 East Avenue South, Suite 200 | La Crosse, WI 54601

Office 608-788-3982 | Toll Free 877-766-3452 | Fax 608-788-3965
 TABLE OF CONTENTS
LEARNING OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ANABOLIC-ANDROGENIC STEROIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
ANDROSTENEDIONE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
HUMAN GROWTH HORMONE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
CREATINE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
BETA-HYDROXY-BETA-METHYLBUTYRATE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
ALCOHOL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
CAFFEINE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
 Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
AMPHETAMINES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
ERYTHROPOIETIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Effects on Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Medical Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Testing and Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
ETHICAL AND LEGAL CONSIDERATIONS FOR THE PHYSICAL THERAPIST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
CASE STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Case Study 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Subjective information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Objective findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Guide to Physical Therapist Practice diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Case Study 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Subjective information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Objective findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Physical therapy diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Physical therapy intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Reevaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Guide to Physical Therapist Practice diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
REVIEW QUESTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Opinions expressed by the authors are their own and do not necessarily reflect the views of the Orthopaedic Section.

The publishers have made every effort to trace the copyright holders for borrowed material.
If we have inadvertently overlooked any, we would be willing to correct the situation at the first opportunity.
© 2006, Orthopaedic Section, APTA, Inc.

Course content is not intended for use by participants outside the scope of their license or regulations. Subsequent use
of management is physical therapy only when performed by a PT or a PTA in accordance with Association policies,
positions, guidelines, standards, and ethical principals and standards.
Ergogenic Substances
Peter A. Huijbregts, PT, MSc, MHSc, DPT, OCS, MTC,
CSCS, FAAOMPT, FCAMT
University of St Augustine for Health Sciences
St Augustine, Fla
The Journal of Manual and Manipulative Therapy
Forest Grove, Ore
Shelbourne Physiotherapy Clinic
Victoria, British Columbia
Dynamic Physical Therapy
Cadillac, Mich
Ellen Pong, BA, MOT, DPT
University of St Augustine for Health Sciences
St Augustine, Fla
NovaCare Rehabilitation
Milton, Fla
LEARNING OBJECTIVES
Upon completion of this monograph, the course par-
ticipant will be able to discuss the following with respect
to ergogenic substances:
1. Data on prevalence of use.
2. Mechanisms of action.
3. Effects on performance.
4. Medical indications.
5. Side effects.
6. Testing procedures.
7. Regulations relating to use.
8. Ethical and legal considerations as related to physi-
cal therapy practice and patients using or suspected
of using the substances discussed.
INTRODUCTION
Ergogenic substances are products used with the aim
of improving athletic performance. One might associate
the use of these products solely with high-level amateur
or professional sports. Recent allegations of erythropoi-
etin use by 7-time Tour de France winner Lance Arm-
strong may come to mind.1 The sudden withdrawal of 27
members of the Chinese team before the 2000 Sydney
Olympics raised suspicions of a state-run doping pro-
gram similar to the one uncovered in the former com-
munist German Democratic Republic.2 Another high-
profile case involved the 1988 Seoul Olympics 100-
meter winner, Ben Johnson, who was stripped of his title
after testing positive for the anabolic steroid stanozolol.2
However, the use of ergogenic substances is by no means
a recent phenomenon.
In the ancient Olympic games, athletes experimented
with special diets to enhance performance. Charmis of
Sparta won the 200-yard race in 668 BC and credited his
performance to a diet of dried figs. The champion mid-
dle-distance runner Dromeus of Stymphalos ate a diet
consisting of only meat. Gladiators in the Roman Colise-
1
um used unspecified stimulants to combat fatigue, as did
medieval knights. To increase their strength and aggres-
sion, the berserkers of Norse mythology used a drug
derived from mushrooms containing muscarine. For cen-
turies, Andean Indians have chewed coca leaves to
increase endurance and stave off mountain sickness.3
In more recent times, Thomas Hicks won the 1904 St
Louis Olympic marathon after openly being adminis-
tered brandy and strychnine as performance-enhancing
stimulants several times during the race. In the 1960
Olympics, cyclist Knut Jensen of Denmark collapsed and
died during competition as a result of amphetamine use.
In the 1967 Tour de France, Tom Simpson of the United
Kingdom died of similar causes, and his became the first
doping-related death to be televised. In the 1980s, mul-
tiple young Dutch professional cyclists died from cardio-
vascular events linked to erythropoietin use. Anabolic
steroid use has become endemic at the Olympics from
1964 onward.3,4 Due to the suspected prevalence of its
use in the absence of a validated test for its detection, the
1996 Atlanta Olympics were dubbed the “Growth Hor-
mone Games.”5
Use of ergogenic substances is not limited to high-lev-
el athletes nor is it limited to adults. The 1991 National
Household Survey on Drug Abuse indicated that over
1 million people in the United States used anabolic
steroids, with a lifetime use of 0.9% in men and 0.1% in
women. More current estimates have indicated there are
as many as 3 million steroid users in the United States.
The studies also indicated that 2.7% to 2.9% of young
American adults have taken anabolic steroids at least
once in their lives. Among adolescents in the United
States, 3% to 12% of boys and 0.5% to 2% of girls are
using anabolic steroids.6 In a 1998 survey of 224 male
high school students, 5% reported the current or past use
of human growth hormone.7 In a more recent survey of
1515 high school students, 2.2% admitted to using the
then legal but now illicit steroid precursor androstene-
dione and 7.6% reported using amphetamines.8
Some ergogenic substances are controlled sub-
stances, meaning they can only be obtained legally with
a physician’s prescription. All controlled and some
uncontrolled substances with an ergogenic potential are
considered doping and are banned by various sporting
organizations. The World Anti-Doping Agency publishes
a yearly updated prohibited list9 that includes prohibited
methods and prohibited classes of substances (Table 1).
However, not all substances used for performance-
enhancing purposes are on this list. Creatine and beta-
hydroxy-beta-methylbutyrate are freely available over-
the-counter nutritional supplements.
Nutritional supplements are regulated in the United
States under the 1994 Dietary Supplement Health and
Education Act. This act defined supplements as distinct
from drugs and food additives, and limited federal con-
trol over marketing claims, purity standards, and content
labeling.7 In 1996, about half of the United States popu-
lation reported the use of some supplements. Supple-
Table 1. 2005 World Anti-Doping Agency Prohibited List 74% of power lifters, boxers, weightlifters, and track and
field athletes reporting the use of this nutritional supple-
Prohibited classes of substances
ment.11 A survey of 1103 middle and high school athletes
Anabolic agents (10 to 18 years) reported 5.6% using creatine with users
• Anabolic-androgenic steroids
from grades 6 to 12.12
• Other anabolic agents
With such high prevalence for the use of both illegal
Hormones and related substances and legal ergogenic substances, the physical therapist
• Erythropoietin
will at some time provide services to patients using these
• Growth hormone, insulin-like growth factor-I,
mechano growth factors substances for performance-enhancing or possibly med-
• Gonadotrophins ical purposes. As with any pharmacological substance,
• Insulin the therapist needs to be aware of intended and adverse
• Corticotrophins effects on the patient and the possible interaction of
β2-agonists these substances with the physical therapy interventions
provided. As many of the substances discussed in this
Anti-estrogenic agents monograph are illegal to use, except on prescription by
Diuretics and other masking agents a physician for medical purposes, and are banned by
Prohibited methods sporting organizations, the authors also have to discuss
Enhancement of oxygen transfer legal and ethical implications. The authors of this mono-
• Blood doping graph do not intend to provide a comprehensive discus-
• Artificial enhancement of oxygen uptake, transport, sion of all substances with ergogenic potential but do
or delivery hope to cover the most common of these products.
Tampering with samples (intravenous infusions, catheteri-
zation, urine substitution) ANABOLIC-ANDROGENIC STEROIDS
Gene doping
Mechanism of Action
The main male sexual hormone is called testosterone.
Substances and methods prohibited in competition
From birth until puberty, plasma testosterone concentra-
Stimulants tion is up to 2 nmol/L. In boys, from about the age of 10,
Narcotics testosterone production increases until, after puberty,
Cannabinoids plasma testosterone levels reach approximately 0.6
mg/dL. In postpubertal women, plasma testosterone lev-
Glucocorticosteroids
els are about 0.03 mg/dL. Ninety-five percent of the
Substances prohibited in particular sports testosterone circulating in the blood is bound to proteins,
Alcohol mainly to sex–hormone-binding globulin and to a lesser
β-blockers extent to albumin. Only 2% to 3% circulates in the form
of free testosterone.13,14
Specified substances
Testosterone production in men is about 8 mg/day
Ephedrine, L-methylamphetamine, methylephedrine (with a range of 4 to 10 mg/day15), of which the Leydig
Cannabinoids cells of the testes produce 90% to 95%. The remainder is
All inhaled β2-agonists except Clenbuterol produced by the adrenal cortex, which is the only source
Probenecid of testosterone in women.13 Testosterone is a so-called C-
19 steroid hormone. In the human body, these steroid
All glucocorticosteroids
hormones are derived from cholesterol. The testosterone
All β-blockers precursor dehydroandrostenedione (DHEA) is converted
Alcohol to the immediate precursor of testosterone (ie,
androstenedione) by the action of the enzyme 3β-hydrox-
ment sales in 1997 amounted to $11.8 billion in the ysteroid dehydrogenase. The enzyme 17β-hydroxysteroid
United States, with a predicted growth of 10% to 14% for dehydrogenase then converts this androstenedione to
2000.10 Supplements do not fall under the jurisdiction of testosterone. Whenever testosterone is produced, its iso-
the US Food and Drug Administration (FDA) and, there- mer epitestosterone is also synthesized. The structure of
fore, the FDA has not evaluated claims as to their effica- epitestosterone is similar to that of testosterone, with the
cy and safety.10 Creatine is probably the most popular of exception of the orientation of the –H and –OH groups at
ergogenic nutritional supplements, with annual sales the 17th carbon atom. In normal men, the ratio of plasma
over $400 million.7 Recent surveys indicate that 28% to concentrations of testosterone to epitestosterone rarely
41% of athletes in the National Collegiate Athletic Asso- exceeds 3:1. In 1 of 1000 men, this ratio is 4:1.16 Devia-
ciation (NCAA) were using creatine, and 29% to 57% of tions from this ratio are considered indicative of exoge-
health club members reported using creatine. Creatine nous supplementation.16 The testes also produce 5α-dihy-
use is even higher in power-sport athletes, with 45% to drotestosterone (DHT), a substance with effects similar to

2
testosterone, and 2 distinctly less biologically active sub-
stances (ie, the testosterone precursor androstenedione
and dehydroepiandrosterone).13
Testosterone is lipid-soluble and, therefore, can freely
cross cell membranes to produce its main effects by
interaction with the cell nucleus. However, interaction
with a cell surface receptor has not been ruled out. In
some cells, testosterone is first converted by the enzyme
5α-reductase to DHT, which then interacts with the
nucleus. In addition to its formation in the testes, as not-
ed above, DHT is formed from testosterone in the liver,
brain, prostate, external genitalia, and, to a very minimal
extent, skeletal muscle. The enzyme aromatase converts
testosterone to estradiol in the liver and the hypothala-
mus. This estradiol is essential for sexual differentiation
of the brain, bone mass consolidation, and epiphyseal
closure. Some testosterone is also converted to estradiol
in the testes. In addition to its conversion to DHT and
estradiol, testosterone is metabolized in the liver to DHT
and androstenedione. These substances are then con-
verted by the 3-keto reductive enzymes (3α and 3β-
ketoreductase) to androsterone or 1 of its 2 isomers,
epiandrosterone or etiocholanolone, which are all
excreted through the kidney in the urine.13
Testosterone is an anabolic-androgenic hormone.
Androgenic actions involve development and mainte-
nance of primary and secondary sexual characteristics.
In utero, testosterone plays a role in the formation of the
internal male genitalia. Dihydrotestosterone has a role in
formation of the external genitalia and the prostate. Sec-
ondary sexual characteristics in men include muscu-
loskeletal configuration, genital size, psychological
changes, and sperm production. Dihydrotestosterone is
the hormone responsible for adult secondary hair
growth.13
In the young, the anabolic actions of testosterone
include stimulation and eventual inhibition of skeletal
growth. Anabolic actions also consist of the inhibition of
urinary nitrogen loss and stimulation of protein synthesis,
mainly in the skeletal muscles, resulting in muscle
growth.13 The increase in muscle size and whole body
protein synthesis is one of the reasons for the weight gain
seen in people using anabolic steroids.14 Anabolic
steroids may also have an anticatabolic effect by inhibi-
tion of the actions of the glucocorticoids that are released
as a result of intense exercise by way of competitive inhi-
bition of the glucocorticoid receptor.16 They also increase
the number of red blood cells14 and may have a direct
neural action on alpha-motor neurons through androgen
receptors.16 In the soft connective tissues, anabolic
steroids enhance collagen synthesis. They also exert a
direct suppressive effect on osteoclasts with a resultant
increase in bone mineral density.6
Testosterone was first chemically synthesized in 1935,
but it was soon discovered that when given orally or
injected, this newly isolated compound was quickly
metabolized in the liver and, thus, inactivated before it
could reach the target organ, which in the case of ath-
3
letes taking the substance for ergogenic purposes is
skeletal muscle.13,17 Testosterone analogs or synthetic
derivatives that might be degraded less rapidly by the
body were developed.13,14 Testosterone can be alkylated
at the 17-α position to produce oral anabolic steroids or
esterified at the 17-β position to form injectable anabol-
ic steroids.14 Table 2 provides an overview of commonly
used oral and injectable anabolic-androgenic steroids
(AAS). Oral and injected doses are the typical method of
delivery in nonelite athletes. Elite athletes also seem to
be using transdermal patches, buccal tablets, nasal
sprays, gels, and creams as delivery methods.14,17 All AAS
possess both anabolic and androgenic activity. When
used for performance-enhancing reasons, the androgenic
effect is obviously an unwanted side effect, especially in
women athletes. The goal for a synthetic testosterone
derivative is to minimize these androgenic effects. Testos-
terone has an anabolic-androgenic ratio of 1:1. This ratio
for nandrolone is 10:1 and for stanozolol it is 30:1. How-
ever, provided AAS are used for a sufficient period at suf-
ficient doses, they will all have masculinizing effects.6
Table 2. Commonly Used Oral and Injectable Anabolic-
androgenic Steroids*
17α-Alkylated Derivatives 17β-Esterified Derivatives
Methandrostenolone Testosterone esters: blend,
Methyltestosterone cypionate, enanthate,
Oxandrolone heptylate, propionate
Oxymetholone Nandrolone esters:
Stanozolol decanoate, phenpropionate
Ethylestrenol Boldenone
Fluoxymesterone Methenolone
Danazol Trenbolone
Stanozolol
Dromostanolone
*Adapted from Evans.6
Physiological replacement levels are common for clin-
ical applications. Participants in strength sports generally
use doses that may be 10 to 100 times that of physiolog-
ical doses, or even more, in an attempt to gain muscle
mass and strength.14 In extreme cases, dosages of 1 to 3
grams per day have been reported.6,15 However, because
illicit AAS frequently contain falsely labeled contents or
even products meant for veterinary use, actual human
dosages are hard to establish.18 Steroid users also use
cycling (episodes of steroid use lasting 6 to 12 weeks),
stacking (use of more than 1 steroid at a time), and pyra-
miding (moving from a low to a higher dose and then
tapering off to a lower dose during a cycle). Steroid users
also often stagger different steroids to avoid developing
tolerance to a particular steroid and combine steroids
with other drugs to combat known side effects.14,15
Effects on Performance
Because AAS are illegal for use as an ergogenic aid in
healthy subjects, there are very few well-controlled stud-
ies.16 The fact that many of the drugs used by athletes are
in fact veterinarian preparations or drugs originating in
other countries, both of which are not FDA approved for
human use, further (justifiably) thwarts any researcher
seeking approval from an institutional review board.19
This probably explains why up until 1987, the American
College of Sports Medicine regarded AAS as effective to
increase strength (in combination with strength training
and proper nutrition) only in some but not all individu-
als.20 More recent studies using supraphysiologic doses
have provided more evidence in support of the anecdo-
tal reports of a positive ergogenic effect. Based on the
physiological actions of testosterone discussed above,
the authors would expect to see AAS use result in
increased strength, greater lean body or muscle mass,
enhanced tendon and muscle repair and regeneration,
increased bone mineral density, and possibly increased
endurance as a result of the increase in the number of
circulating erythrocytes. The anticatabolic effects on glu-
cocorticoid action may also play an ergogenic role by
allowing for higher training intensity.
Over a 6-week period, Friedl et al21 administered 100
or 300 milligrams per week of testosterone enanthate
(TE) or 19-nortestosterone decanoate to eugonadal
young men. This resulted in insignificant pretest to
posttest increases in isokinetic elbow flexor and knee
extensor strength, with a trend to greater and more con-
sistent strength gain occurring in the high-dose TE group.
The low-dose TE group (considered in this study as a
replacement dose) did not increase body weight; the oth-
er groups gained, on average, 3 kilograms. Percentage of
body fat did not change in any group, but there were sig-
nificant increases in upper body circumference measure-
ments in the 2 high-dose groups. The authors concluded
that androgens at greater than replacement doses
increase body mass and may increase strength in normal
men but that changes are highly variable.
Bhasin et al22 randomized 61 eugonadal men (18 to
35 years) to 5 different groups that received 20 weekly
injections of either 25, 50, 125, 300, or 600 milligrams
of TE. Endogenous testosterone production was chemi-
cally suppressed during the study and the subjects
refrained from strength training or moderate to heavy
endurance exercise. Fat-free mass and thigh and quadri-
ceps muscle volume increased significantly in the 125,
300, and 600 milligrams per week groups. Leg press
strength increased significantly in the 50, 300, and 600
milligrams per week groups; leg power increased signif-
icantly in the 300 and 600 milligrams per week groups.
All changes were correlated significantly with testos-
terone levels during treatment.
Bhasin et al23 randomly assigned 43 experienced men
weightlifters (19 to 40 years) to 1 of 4 groups: placebo
without progressive resistance exercise, 10 weekly 600
milligram TE injections without exercise, placebo plus
exercise, and TE injections plus exercise. In the no-exer-
cise groups, the men receiving AAS had significantly
greater increases over placebo in triceps and quadriceps
4
cross-sectional area and in bench press and squat 1-rep-
etition maximum (1-RM) loads. The men assigned to the
exercise and AAS group had significantly greater increas-
es in fat-free body mass and triceps and quadriceps
cross-sectional area than those in both no-exercise
groups. The 1-RM load in the bench press increased by
22 ± 2 kg for the bench press and 38 ± 4 kg for the squat
exercise in the AAS and exercise group, a significant dif-
ference again as compared to the no-exercise groups.
The changes in quadriceps cross-sectional area and
1-RM load on the squat were significantly greater in the
AAS and exercise group as compared to all other groups.
In a cross-sectional study, Alway19 compared the
elbow flexors of elite women bodybuilders using AAS
(29.7 ± 3.5 years) to those of elite women bodybuilders
not using these substances (34.6 ± 2.3 years) and con-
trols (25.6 ± 3.3 years). He found significantly greater
cross-sectional area for the biceps, greater hypertrophy
of type I and II fibers, a greater amount of concentric
work during 25 repetitions of isokinetic elbow flexion,
and less percentage fatigue during these 25 repetitions
for the AAS users as compared to both other groups.
Maximal torque was the same for AAS users and nonus-
ing bodybuilders. The AAS users also had significantly
greater whole-body lean body mass and less body fat
than the other 2 groups.
Blazevich and Giorgi24 compared 12 weeks of place-
bo to 3.5 mg/kg TE during resistance training for the tri-
ceps brachii in healthy men. The 1-RM load for the
bench press and the angle of pennation in the triceps
muscle increased significantly in the AAS group over the
placebo group, suggesting a role for possible AAS-
induced changes in muscle architecture for the strength
gains observed with AAS use.
Tamaki et al25 administered nandrolone decanoate
(ND) to adult male rats and subjected them to a resis-
tance-training stimulus. Chemical markers of postexercise
muscle damage were lower and recovered faster in AAS-
treated rats, while work capacity and resistance to muscle
fatigue were higher as compared to a control group.
Beiner et al26 studied the effects of ND on the course
of recovery after a contusion injury to the gastrocnemius
muscle in rats. They found that AAS compared to corti-
costeroids resulted in significantly greater force-generat-
ing capacity and associated better histological appear-
ance at 14 days and suggested a possible role for AAS in
the treatment of muscle injury.
Äärimaa et al27 reported on 33 subjects with a surgi-
cally repaired rupture of the pectoralis major. They found
that the only factor that statistically correlated with a pos-
itive outcome was the patient using AAS (cumulative
odds ratio = 5.1; 95% confidence interval, 1.1-23.3; P =
.033).
Triantafillopoulos et al28 subjected human tendons to
either ND, loading, ND and loading, or no loading and
no ND. The AAS with loading group showed the greatest
level of remodeling and the best-organized actin
cytoskeleton. Mechanical characteristics (ultimate stress
and strain and strain energy density) in the AAS with Side Effects
loading group were significantly greater than in the oth- The use of AAS has been associated with adverse
er 3 groups. effects on multiple organ systems. Table 3 provides an
In summary, the literature reviewed here supports
dose-dependent positive effects of supraphysiologic dos- Table 3. Side Effects Associated With Anabolic-
es of AAS on measures of strength, fat-free mass, and androgenic Steroid Use6,13,16,18,27,31–34
muscle mass.21,22 Concurrent resistance training further Cardiovascular Hypertension
enhances these effects.19,23,24 The literature reviewed also Left ventricular hypertrophy
seems to indicate possible positive effects on anaerobic Impaired diastolic filling
work capacity and resistance to fatigue during this type Arrhythmia
of exertion.19,25 In vitro research,28 animal research,25,26 Erythrocytosis
Increased blood volume
and a retrospective case series27 support a positive role Edema
for AAS on tendon and muscle repair and regeneration. Thrombosis
Strength gain with AAS may partly be due to changes in Negative impact on blood lipid profile
muscle architecture. Atherosclerosis
Increased C-reactive protein levels
Medical Indications Increased risk of myocardial infarction
Increased risk of sudden death
Anabolic-androgenic steroids have been used med-
ically for androgen replacement therapy in hypogonadal Dermatological Acne
Striae
men or in men after surgical orchiectomy due to testicu-
Alopecia
lar tumors. In young men, they may be given to stimulate Hirsutism
sexual development in cases of delayed puberty or to
Reproductive In men:
increase growth. Women may receive AAS for a condi- Hypogonadism
tion known as sexual infantilism, where a young woman Testicular atrophy
fails to secrete estradiol, progesterone, and testosterone. Reduced sperm count
In postmenopausal women, it has been used to restore Decreased sperm motility
libido.13 Abnormal sperm morphology
Infertility
Initial medical use of AAS included attempts to stim-
Changed libido
ulate weight gain in concentration camp survivors after Gynaecomastia
World War II.13,15 Anabolic-androgenic steroids have also
In women:
been used to increase body weight, muscle mass, and Hirsutism
strength in eugonadal patients with secondary wasting Increased facial hair
syndromes (eg, as a result of human immunodeficiency Deeper voice
virus and acquired immunodeficiency syndrome).6,13 Sat- Clitoral hypertrophy
tler et al29 noted a significant increase in lean body mass Oligomenorrhea
Amenorrhea
in two groups of men with human immunodeficiency
Decreased breast size
virus infection that received 16 weeks of ND injections Male-pattern baldness
whether or not they participated in a resistance-training
Psychological Depression
program. However, the AAS with training group Mania or hypomania
increased lean body mass to a significantly greater Psychosis
degree than the group just receiving ND. In large doses, Aggression
AAS are sometimes used to treat therapy-resistant anemia Withdrawal symptoms
in men.13 Dependence
Anabolic-androgenic steroids are also used to aug- Suicide and homicide
ment muscle mass in the elderly and to prevent the age- Gastrointestinal Elevated liver enzymes
related sarcopenia that contributes to frailty and falls.6 Hepatic carcinoma
Hepatitis A and B
They may also have a role in the treatment of osteoporo- Jaundice
sis.13 Hedström et al30 found significant between-group
Orthopaedic Injection-related intramuscular fibrosis
differences favoring a group of elderly women after hip Injection-related dystrophic calcification
fracture receiving 1 year of ND, vitamin D, and calcium Needle-stick injury to nerves
supplementation over calcium supplementation alone. Tendon rupture
The group receiving AAS had significantly better Harris Posttraumatic compartment syndrome
hip scores, gait speed, maintenance of muscle volume in Administration- Local infection at the injection site
the operated leg, increased muscle volume in the non- related Bacterial abscess
operated leg, and less bone mineral density loss than the Septic arthritis
calcium group. In the future, AAS may also have further Septic shock
Human immunodeficiency virus infection
orthopaedic indications in the area of muscle and tendon
Hepatitis A and B infection
healing.6

5
overview of reported side effects.6,13,16,18,27,31–34 Side effects
considered relatively minor are quite common in AAS
users.6 Acne affects 40% to 54% of users; testicular atro-
phy, 40% to 51%; gynaecomastia, 10% to 34%; cuta-
neous striae, 34%; and reported injection-site pain, 36%.
Orally administered rather than injectable AAS may
have a more deleterious effect on liver enzymes6 and on
blood lipid profiles.29,31 Hartgens et al31 found no effect on
blood lipid profiles in men bodybuilders after using
injectable ND for 8 weeks. Sattler et al29 similarly found
no effect on total cholesterol, low-density lipoprotein
cholesterol, low-density lipoprotein phenotype, or fasting
triglyceride levels in a study of men with human immun-
odeficiency virus infection using ND with or without
exercise, as described above. In fact, they found transient
favorable changes in low-density lipoprotein particle size
and high-density lipoprotein cholesterol, triglyceride, and
lipoprotein-A levels in both groups. In contrast, Hartgens
et al31 did find significant adverse effects on blood lipid
profiles in experienced bodybuilders self-administering
multidrug regimens including both oral and injectable
AAS variants. Both studies29,31 noted an unexpected signif-
icant decrease in lipoprotein-A levels. This particle is an
independent risk factor for atherogenesis.
The hypogonadal state induced in men by the admin-
istration of exogenous testosterone derivatives is general-
ly reversible, but it may take 3 to 12 months for endoge-
nous testosterone production and spermatogenesis to
resume. Hypogonadism induced by AAS may require
hormone treatment. Some of the masculinizing effects
noted in Table 3 for women using AAS are permanent (a
deeper voice and facial hair growth), and male-pattern
baldness may persist even after discontinuation of AAS.6
The psychological effects of AAS are less clear. Place-
bo-controlled trials have indicated that 5% of users will
develop manic or hypomanic reactions, with an
increased likelihood of psychiatric effects in subjects
with a prior psychiatric history or a history of alcohol or
drug abuse.6 Some authors13,17,18 noted that expectations
about increased aggression and the influence of person-
ality type in people apt to use these drugs may be the
main reason for roid rage. Brower18 found no evidence of
dependence in medical users of AAS but noted 165
reports in the medical literature of AAS dependence in
nonmedical users. He also warned of the high incidence
of homicide and suicide among AAS users and recom-
mended treatment for withdrawal symptoms including
psychotherapy and medication.
Tendon rupture has been associated with steroid use
based on case reports.6 Earlier we discussed the in vitro
evidence for the positive effect AAS may have on the
mechanical characteristics of tendons.28 Anabolic-andro-
genic steroids may predispose tendons to failure by alter-
ing their crimp pattern and biomechanical properties.28
This results in a stiffer, less elastic tendon, but one with
the same ultimate tensile strength.6 It is assumed that ten-
dons are mainly indirectly at greater risk of rupture only
6
because the slower adapting, less vascular tendons may
not be able to keep up with the increase in force-gener-
ating capacity caused by the more rapid AAS-induced
hypertrophy and strength changes in skeletal muscle.6,28
Skeletally immature AAS users face additional risks.
Exogenous testosterone administration, if not under care-
ful medical supervision, can lead to premature closure of
the epiphyses with decreased bone growth and develop-
ment. This side effect persists up to 3 months after discon-
tinuation of the drugs.13 Up to 25% of adolescent AAS
users engage in needle sharing, with the associated risk of
transmission of blood-borne pathogens such as human
immunodeficiency virus and hepatitis B and C.16 Combin-
ing AAS with other drugs is also common among adoles-
cent users.14 Simultaneous use of amphetamines and AAS
increases the chance of cardiotoxicity. Cocaine-related
seizures and heart rate increases are potentiated by AAS.18
Manoharan et al35 described a young bodybuilder in
whom AAS combined with bromocriptine, a dopamine
agonist with a possible positive effect on body fat content,
resulted in bradycardia and syncopal episodes. Perhaps
the most bottom-line approach to the adverse effects was
the study that indicated that chronic AAS users had a 4.6
times higher risk of mortality than nonusers.6
Testing and Regulation
Anabolic-androgenic steroids are a Schedule III con-
trolled substance.18 This means that they are legally avail-
able only with a physician’s prescription. They are
banned and tested for by the International Olympic
Committee (IOC) and most United States sporting associ-
ations, including the National Basketball Association, the
NCAA, and the National Football League.16 Up until
recently, Major League Baseball did not test for these
drugs. Recent claims by former players and congression-
al hearings on the topic of steroid use in America’s
favorite pastime16 have resulted in a drug-testing program.
Testing for AAS suffers from considerable variation in
what is considered a normal result. The tests are expen-
sive and a positive result is often contested in court with
great financial ramifications. Newer versions of drugs
that go undetected with current testing are being devel-
oped constantly; currently, the designer AAS tetra-hydro-
gestrinone is under intense scrutiny. The impact of legal
matters on testing is exemplified by what is considered a
negative test result. We discussed the normal testos-
terone-epitestosterone ratio above. According to the IOC
Anti-Doping Code, a positive test for exogenous testos-
terone supplementation in men and women is a test with
a ratio ≥6:1. As discussed, a normal ratio for men is 3:1,
with only 1 in 1000 men having a ratio of 4:1.16 Table 4
provides the take-home message for AAS.
ANDROSTENEDIONE
Mechanism of Action
Androstenedione is part of a class of androgenic
steroids known as prohormones or steroid precursors.36,37
Steroid precursors either are converted directly to testos-
Table 4. Take-home Message for Androgenic-Anabolic
Steroids
• Androgenic-anabolic steroids (AAS) are synthetic deriv-
atives of the male sex hormone testosterone.
• Supraphysiologic doses of AAS have a proven positive
effect on strength, fat-free mass, and muscle mass. Con-
current resistance training further augments these
effects.
• AAS may have positive effects on anaerobic work capac-
ity, resistance to fatigue during anaerobic exertions, ten-
don and muscle healing, and bone mineral density.
• AAS have proven adverse side effects affecting multiple
organ systems. These adverse effects range from minor
temporary complications to sudden cardiac death.
• The skeletally immature and women athletes using AAS
are especially at risk for irreversible adverse effects.
• AAS are only legally available on a physician’s prescrip-
tion. They are banned and tested for by all major sport-
ing organizations and valid tests exist for their detection.
terone or they form androgen-like derivatives (ie, AAS
such as nandrolone).36 The class of steroid precursors
includes androstenedione, DHEA, 5-androstenedione,
4-androstenediol, 5-androstenediol, 19-norandrost-
4-enedione, 19-norandrost-5-enediol, and 19-norand-
rost-4-enediol.36,38,39 In vitro evidence indicates that and-
rostenedione, 5-androstenediol, and possibly 4-andros-
tenediol, all are direct chemical precursors to testos-
terone.36 As is the case for testosterone, endogenous pro-
duction of androstenedione peaks in one’s mid-20s and
declines after the third decade.37 Women produce some
33% more androstenedione than do men.39 The authors
have discussed further details on the metabolism of
androstenedione and testosterone earlier in the section
on AAS.
Steroid precursors have little affinity for androgen
receptors and, therefore, little androgenic and anabolic
action by themselves.37 The anabolic action of
androstenedione is about 10% to 20% that of testos-
terone.39 Therefore, the hypothesized mechanism of
action for androstenedione as an ergogenic substance is
that increased levels of this testosterone precursor will
lead to increased serum levels of testosterone, with the
resultant performance-enhancing effects, as discussed
earlier. Before looking at actual effects on performance
and body composition, it is very relevant to test this
hypothesis by examining the in vivo effect of androstene-
dione supplementation on blood hormone levels with or
without exercise.
King et al40 administered 300 mg/day of androstene-
dione or placebo to 30 eugonadal men (19 to 29 years)
and noted no between-group differences in serum free
testosterone, luteinizing hormone, or follicle-stimulating
hormone blood levels but did note a significantly larger
increase in estradiol and estrone levels in the
androstenedione group.
Leder et al41 administered 0, 100, or 300 mg/day of
androstenedione for 7 days to eugonadal men (20 to 40
7
years). They found an increase of whole-day mean (± SE)
serum testosterone changes of -2 ± 7%, -4 ± 4%, and 34
± 14% for the 0, 100, and 300 mg/day groups, respec-
tively. This represented a significant increase only in the
300 versus the 0 mg/day group. They also found an
increase of whole day mean (± SE) serum estradiol
changes of 4 ± 6%, 42 ± 12%, and 128 ± 24% in these
same groups. Both supplementation groups significantly
increased serum estradiol levels as compared to the no-
supplementation group. The study reported no changes
in estrone, luteinizing hormone, and follicle-stimulating
hormone levels, but the authors of the study did com-
ment on the large interindividual differences in estro-
genic and androgenic responses to androstenedione sup-
plementation.
Earnest et al42 administered 200 mg/day of 4-
androstene-3,17-dione, 200 mg/day of 4-androstene-3
beta,17 beta-diol, or placebo to 8 men (23.8 ± 3 years).
They noted a significant increase in total and free serum
testosterone only in the androstenedione group for 90
minutes after supplementation.
Broeder et al43 provided 50 men (35 to 65 years) with
either placebo, 200 mg/day of oral androstenediol, or
200 mg/day of oral androstenedione for 12 weeks while
they participated in a high-intensity resistance-training
program. Both supplementation groups had significant
increases in blood levels of estrone and estradiol.
Androstenedione supplementation resulted in a signifi-
cant increase in total testosterone levels by 16% after 1
month. At 12 weeks, these levels had returned to pre-
treatment levels, partly due to a down-regulation in
endogenous testosterone synthesis as a result of 18% to
33% attenuation in luteinizing hormone levels.
Ballantyne et al44 administered 200 mg/day of oral
androstenedione or placebo for 2 days to 10 men. On the
second day, the subjects performed heavy-resistance exer-
cise. They found no significant between-group differences
for serum testosterone levels but a significant increase in
luteinizing hormone after supplementation and estradiol
levels after exercise in the androstenedione group.
Brown et al45 provided placebo or daily doses of 300
mg androstenedione, 150 mg DHEA, 750 mg Tribulus
terrestris, 625 mg chrysin, 300 mg indole-3-carbinol,
and 540 mg saw palmetto for 6 of 8 weeks with subjects
performing resistance exercise 3 days a week for 8
weeks. They noted no change in serum free or total
testosterone concentrations in either group but did note
significant increases in serum estradiol and estrone lev-
els in the supplementation group.
In summary, androstenedione supplementation at 300
mg/day seems to have the potential to increase serum
testosterone levels in some individuals but is also associ-
ated with an increase in serum estrone and estradiol lev-
els, substances both not known for their ergogenic
potential. This estrogen release may be potentiated by
resistance exercise. The authors previously discussed the
conversion of testosterone by the enzyme aromatase to
estradiol in the liver, hypothalamus, and testes. Consid-
erable interindividual variations in this androgenic and
estrogenic response make it hard to make definitive
statements on the hypothesized testosterone-related
mechanism of action for androstenedione. The testos-
terone response to androstenedione supplementation
may be different in women and hypogonadal men.40
Androstenedione is usually taken as an oral capsule.
Doses recommended for performance-enhancing pur-
poses vary from 100 to over 1200 mg/day.38,39 One
hypothesis for the discussed lack of efficacy for
androstenedione is the significant first-pass hepatic
metabolism to which oral supplements are subjected:
only 2% of an oral dose is converted to testosterone.46
Androstenedione is also available as a sublingual spray,
transdermal patch, percutaneous gel, or oil-based
injectable variant.38,39
Effects on Performance
Based on its hypothesized mechanism of action for
which the lack of evidence was discussed above,
androstenedione supplementation would be expected to
have the same ergogenic effects as AAS.
Beckham et al47 found no significant changes in body
composition or body mass in men (44.1 ± 3 years) sup-
plemented with 200 mg/day of androstenedione or
placebo for a period of 28 days.
In the study discussed earlier, King et al40 found no
significant between-group differences with regard to the
1-RM load with knee extension, mean increase in type II
fiber cross-sectional area, increase in lean body mass, or
decrease in fat mass with exercise and placebo or 300
mg/day supplementation with androstenedione.
In the study discussed above, Broeder et al43 found no
between-group differences for muscle strength or body
composition measures after 12 weeks of resistance train-
ing and supplementation with 200 mg/day of andros-
tenedione, androstenediol, or placebo.
Similarly, Brown et al45 found no between-group dif-
ferences in muscle strength gain after 8 weeks of resis-
tance training and supplementation with a combination
of 300 mg/day of androstenedione, 150 mg/day of
DHEA, and herbal substances, or placebo.
In summary, the evidence reviewed above does not
support an ergogenic effect of androstenedione supple-
mentation of up to 300 mg/day on parameters of strength
or body composition. Powers,37 after a review of the lit-
erature, concluded that the available scientific data did
not support ergogenic claims for androstenedione sup-
plementation. Yesalis38 commented on the possible role
that using inexperienced weightlifters for studies on
androstenedione supplementation may have had and
hypothesized a possible ergogenic role in more experi-
enced strength athletes.
Medical Indications
The literature reviewed did not provide indications for
the medical use of androstenedione. Considering its
8
unpredictable and highly variable effect on multiple
serum hormone levels, this should hardly be surprising.
Side Effects
Without providing evidence, some authors have
hypothesized that the adverse effects of androstenedione
are likely similar to those of AAS.37,39,41,48 In a case report,
Battista et al49 linked bilateral asynchronous Achilles ten-
don ruptures to the use of androstenediol in a 35-year
old bodybuilder. The authors discussed the effects of
androstenedione on estrogenic hormones. Increased
estrogen levels have been linked with increased cardio-
vascular risk.39,40 Increased estradiol levels have been
linked to breast cancer in women and to pancreatic can-
cer in men. Increased serum levels of androstenedione
have been linked to prostate and pancreatic cancer.40
Increased estrogenic levels may produce feminizing
effects in men using androstenedione (eg, gynaecomas-
tia).37,39 Yesalis and Bahrke39 warned about possible
adverse hepatic effects of long-term androstenedione
use.
As for true evidence of adverse action, Beckham and
Earnest47 reported no effect of androstenedione supple-
mentation on mood state and noted no reports of
changes in libido or acne, which are frequently associat-
ed with the use of AAS. King et al40 noted a significant
decrease in high-density lipoprotein cholesterol levels in
androstenedione users when compared to placebo.
Beckham and Earnest47 found no significant effects on
lipid profile for androstenedione supplementation but
did note a nonsignificant 13% reduction in high-density
lipoprotein cholesterol. In his review, Powers37 noted
reports of a 12% to 20% reduction in high-density
lipoprotein cholesterol. Broeder et al43 reported signifi-
cant adverse effects on high-density lipoprotein-C cho-
lesterol levels, coronary heart risk disease, and blood
lipid ratios.
Testing and Regulation
In 1996, androstenedione became available as an
over-the-counter nutritional supplement.46 Mark McG-
wire’s admission that he used androstenedione as a per-
formance-enhancing substance during his 1998 race to
break the home run record catapulted sales of this steroid
precursor.38 Since October of 2004, androstenedione and
other steroid precursors (with the exception of DHEA,
estrogens, progestins, and corticosteroids) are classified
as Schedule III controlled substances.48 The IOC, the
National Football League, and the NCAA have all
banned androstenedione.
As for testing, ingestion of androstenedione would
likely cause athletes to test positive for steroid use, as it
results in increased urinary concentrations of andros-
terone, etiocholanolone, and hydroxylated derivatives of
both substances; testosterone; and epitestosterone. These
substances will cause an increased testosterone-to-
epitestosterone ratio and a positive test for AAS.36 The fact
that some one-time commercially available supplements
in fact contained 19-norandrostenedione or even testos-
terone further increases the likelihood of a positive test.50
Table 5 provides the take-home message for androstene-
dione.
Table 5. Take-home Message for Androstenedione
• The scientific evidence reviewed does not support
claims for an ergogenic effect of androstenedione sup-
plementation.
• Androstenedione supplementation has shown to
increase cardiovascular health risks related to altered
blood lipid profiles and elevated estradiol and estrone
levels.
• Androstenedione is a controlled substance and banned
for use by most sporting organizations. Its ingestion will
likely result in tests positive for the use of androgenic-
anabolic steroids.
HUMAN GROWTH HORMONE
Mechanism of Action
Human growth hormone (hGH), or somatotropin, is a
polypeptide hormone released from the somatotroph
cells in the anterior pituitary gland.5,51 Secretion is
episodic and pulsatile. There are approximately 10 puls-
es of hGH secretion throughout the day interspersed by
128-minute intervals where serum hGH levels are near-
ly undetectable.52 The highest levels occur some 60 to 90
minutes after the onset of sleep.5 In young adults, serum
concentrations vary from 0.1 to 30 mg/L or higher.53
Endogenous hGH exists in many molecular forms.51,54 The
main pituitary molecular weight variant is a 191-amino
acid, 22kDa form that represents about 21% of plasma
hGH. However, as a result of posttranslational and post-
secretory modifications, endogenous hGH has a great
molecular heterogeneity with many aggregates and frag-
ments existing in the circulation with possible indepen-
dent and specific roles.51
Release of hGH is under the control of 2 hypothala-
mic hormones. Somatostatin inhibits secretion and
somatocrinin (or growth hormone-releasing hormone)
stimulates secretion.5,51 Estradiol also stimulates hGH
release; testosterone has little effect. Drugs that stimulate
α2-adrenergic receptors (eg, clonidine) increase hGH
secretion; drugs that stimulate β-receptors (eg, salbuta-
mol) decrease secretion.5 Arginine, insulin-induced
hypoglycemia, and γ-hydroxybutyrate also increase
secretion.5 Serotonin, dopamine, and gamma-aminobu-
tyric acid receptor stimulation all also lead to an increase
in hGH release. Cortisol, insulin-like growth factor-I
(IGF-I), and hGH itself all inhibit secretion. Secretion is
lower in elderly, postmenopausal, and obese individu-
als.52 The 24-hour serum hGH levels in men and women
over age 55 are one third of those of individuals ages 18
to 33.53 Exercise can increase hGH production fivefold to
tenfold;55 within 20 minutes of beginning aerobic exer-
cise at 75% to 90% of maximum oxygen consumption
9
(VO2max), hGH levels rise. More intense exercise results
in earlier hGH secretion, and intermittent intense exer-
cise supposedly produces the highest hGH levels.5 The
effect of aerobic exercise is greater than that of resistance
exercise.54 The hGH plasma half-life is only 12 to 45 min-
utes, and hGH is metabolized in the liver.5
Receptors for hGH are present on every cell in the
body. Its most obvious action is stimulation of somatic
growth in preadolescents. In children, hGH promotes
amino acid uptake and protein synthesis, resulting in
length and cross-sectional muscle fiber growth. Bone
growth occurs by way of stimulation of cartilage prolifer-
ation in the epiphyseal plates. In adults, hGH and IGF-I
stimulate osteoclast differentiation and activity, resulting
in increased bone remodeling and increased bone min-
eral density.52
Human growth hormone also has metabolic effects
on the homeostatic regulation of fuel storage and usage,
but this role is less clear, as is its exact role in adults.5
Determining the unique role of hGH is further compli-
cated because hGH stimulates the mainly hepatic
release of 2 further hormonal polypeptides: IGF-I and
IGF-II.51 Many of the effects of hGH are thought to be
mediated by IGF-I.5,51 Metabolic effects of hGH in the
acute phase include increased activity of muscle mem-
brane amino acid transport mechanisms with resultant
increased amino acid uptake into the muscle and
increased glucose uptake in the muscle and adipose tis-
sue with reduced fat metabolism. Insulin-like growth fac-
tor-I mediates the second phase with quite a contrary
effect: increased lipolysis in adipose tissue results in
increased fatty acid utilization and glucose sparing.5
Lipolysis is also brought about by an hGH-mediated
increase in other lipolytic hormones and by increasing
responsiveness of the adipocyte to these other hormones.
Lipogenesis is decreased by an hGH-mediated inhibition
of some key lipogenic enzymes.51 These combined
effects of hGH on fat and protein metabolism result over-
all in a decrease in adipose tissue mass and an increase
in lean body mass.5,51
Administration of hGH is by way of intramuscular or
subcutaneous injection or by way of an implanted
biodegradable microsphere.5,51 Because of possible cont-
amination of human-derived hGH with the prion causing
Creutzfeldt-Jacob disease, hGH is now produced syn-
thetically.51,55 A number of pharmaceutical companies
have developed recombinant hGH (rhGH) products with
the generic name of somatropin. Brand names include
Protropin, Nutropin, Nutropin AQ, Norditropin, Geno-
tropin, Humatrope, Serostim, and Saizen.51 In the United
Kingdom, the prescribed replacement dose in hGH-defi-
cient children is 0.6 IU/kg body weight per week. People
who abuse hGH for performance enhancement may use
up to 10 times this dose.5 Stacy et al55 reported that dos-
es used by athletes are often even 20 times those pre-
scribed and range up to 5 mg/day.
Effects on Performance
The effects of hGH and IGF-I on fat, protein, and bone
metabolism discussed above explain a potential perfor-
mance-enhancing effect for hGH administration with
regard to body composition, strength, and bone mineral
density. Potentially serious side effects pose ethical limi-
tations with regard to performing research that involves
hGH administration to healthy individuals. Therefore, the
research on the performance-enhancing effects of hGH
administration in athletes is very limited.55
Deyssig et al56 provided either placebo or 0.09
IU/kg/day of hGH to men who were power athletes (23.4
± 0.5 years) for a period of 6 weeks. They controlled for
simultaneous use of AAS. They showed no significant
between-group differences for concentric strength of the
biceps and quadriceps muscles or body weight and body
fat.
Yarasheski et al57 administered a placebo injection or
40 mg/kg/day of rhGH to young men (21 to 34 years)
participating in heavy-resistance exercise for 12 weeks.
The study showed no between-group differences in mus-
cle strength, muscle size, or muscle protein synthesis but
did show a larger increase in lean body mass in the rhGH
group, which was attributed to an increase in noncon-
tractile proteins.
Yarasheski et al58 administered 40 mg/kg/day of rhGH
to men who were experienced weightlifters (23 ± 2
years) for 14 days and found no increase in the rate of
muscle protein synthesis and no decrease in the rate of
whole-body protein breakdown, indicating no effect of
short-term hGH supplementation on muscle protein
metabolism in this specific group.
Medical Indications
Inadequate pituitary hGH secretion may be the cause
of dwarfism, a situation where a child’s rate of growth is
below the 90th percentile for the child’s age. Pituitary
dwarfism is treated by administering rhGH before the
end of puberty, with careful attention to prevention of
secondary diabetes or skin hyperplasia.5 Growth failure
due to chronic renal insufficiency or Turner syndrome is
also treated with hGH administration.55
A further accepted medical use in adults is for the
muscle wasting associated with acquired immunodefi-
ciency syndrome.55 Schambelan et al59 randomized 178
subjects infected with human immunodeficiency virus
with unintentional weight loss greater than 10% of body
weight or body weight less than 90% of the ideal weight
into a placebo group and a group receiving 0.1
mg/kg/day hGH for 12 weeks. The study produced sig-
nificant between-group differences, with a greater
decrease in body fat and greater increases in body
weight, lean body mass, and work output on a treadmill
test to volitional exhaustion in the hGH group.
The decrease in hGH levels with age, reported above,
has also led to the administration of hGH to affect
changes associated with normal aging (ie, a reduction in
lean body mass, bone mass, and skin thickness and an
10
increase in fat mass). Rudman et al60 administered 0.03
mg/kg of hGH 3 times a week to 12 men aged 61 to 81
with low plasma IGF-I levels for 6 months and found sig-
nificant increases in lean body mass and average lumbar
vertebral body mass and a decrease in adipose tissue
mass when compared to age-matched subjects. Yarashes-
ki et al61 administered placebo or 12.5 to 24 mg/kg/day
hGH to healthy, sedentary men aged 67 ± 1 years with
low serum IGF-I levels for 16 weeks. Both groups partic-
ipated in a heavy-resistance program. There were no
between-group differences in muscle strength noted, but
there was a greater increase in fat-free mass in the hGH
group, possibly due to an increase in noncontractile pro-
tein synthesis and fluid retention. Yarasheski et al62 also
studied the effect of daily administration of 12.5 to 18
mg/kg/day hGH versus placebo during 16 weeks of
heavy-resistance training in men aged 67 ± 1 years. They
found no between-group differences in whole body,
spine, or hip measures of bone mineral density. A review
of the effects of hGH supplementation in the subjects
over 60 years did not show favorable additional results
on muscle mass or strength over resistance training
alone.63
Side Effects
Most of the known side effects of hGH abuse have
been obtained from studying medical conditions that
result in its excessive production.51 Acromegaly is a con-
dition that results from hGH oversecretion, mainly in
middle-aged adults and frequently due to a benign ade-
noma of the anterior pituitary gland. In prepubertal and
adolescent children, hGH oversecretion leads to a med-
ical condition called gigantism. However, in adults, the
epiphyses have fused and the affected individual does
not grow taller. Instead the internal organs enlarge, the
fingers grow, and the skin thickens.5 Acromegaly also
causes increases in total body water, calcium, sodium,
potassium, and phosphorus content. Oversecretion may
cause facial and aural soft tissue swelling; hyperhidrosis;
a deeper voice; growth of the ribs, mandible, and frontal
bones; bony overgrowth of the frontal sinuses, vertebral
bodies, and phalanges; widening of the joint space due
to a disproportionate expansion of mechanically dys-
functional cartilage and subsequent premature
osteoarthritis; diabetes mellitus with insulin resistance,
hyperinsulinemia and impaired glucose tolerance;
headache; vision loss; sleep apnea; nerve entrapments;
hypertrophic neuropathy; myopathy; menstrual abnor-
malities; and secretory changes of adreno-corticotropic
hormone, thyroid-stimulating hormone, and vaso-
pressin.51,52 Treatment with rhGH has been shown to
increase the incidence of leukemia.51
Studies on hGH abuse with the aim of performance
enhancement have shown muscle weakness despite
increased size, hyperlipidemia, diabetes, arthritis, and
impotence. Cardiomegaly is often a cause of death in
people abusing hGH. The increased serum levels of free
fatty acids due to hGH administration can promote car-
diac arrhythmia.54 Metabolic acidemia seems to result in
decreased rather than improved exercise performance.
Decreased glycogen storage in the muscle and liver due
to increased hGH levels make recovery from exercise
more difficult.54 The increased protein synthesis with hGH
abuse also results in a thickening and coarsening of the
skin leading to a condition called elephant epidermis.
Other skin effects include increased dermal viscosity and
increased incidence of skin nevi.5 The authors already
mentioned the chance of contracting Creutzfeldt-Jacob
disease from human-derived hGH.5 Stacy et al55 noted
that further research on supraphysiologic hGH adminis-
tration is needed to clarify the prevalence of side effects.
Also, we should bear in mind that rhGH is very
expensive; the cost of a therapeutically worthwhile year-
ly dose runs from $30 000 to $50 000.5,51 Evidence indi-
cates that a lot of the illicit hGH is counterfeit, adulterat-
ed, or of animal origin, containing other peptide hor-
mones, anabolic steroids, and bovine hGH (which has
no effect in humans).5 The risk of injection and of
unknown substances combined with the potentially
lethal side effects observed in clinical conditions with
hGH oversecretion make the abuse of hGH a very dan-
gerous practice.
Testing and Regulation
As also noted by Rennie,54 an Internet search for
“growth hormone” produces a multitude of Web pages
touting the rejuvenating and muscle-building benefits of
this substance. This may in part be due to the stance of
international regulating sports agencies and the highly
publicized search for a valid test to detect hGH abuse.54
The IOC and other sport-governing bodies have banned
the use of rhGH.51 Tests have been developed that rely on
the immunological differences between endogenous and
recombinant hGH, but these tests cannot identify
increased endogenous hGH levels that result from the
injection of human cadaveric hGH or hGH released by
the action of drugs with an effect on pituitary secretion.
Another radio-immunoassay test can detect increases in
plasma constituents affected by hGH secretion or injec-
tion. However, both tests require blood samples, which
has legal and religious implications in many countries.5
Increased urinary hGH levels indicative of rhGH abuse
return to normal after 24 hours, making timing of a urine
test (random versus staged testing) crucial.51 A further
confounding factor is the large interindividual variation
in hGH levels, especially in trained endurance athletes.5
The possible future development of orally administered
hGH-releasing substances further complicates testing.5
At this time, no legally or scientifically valid test exists to
detect hGH abuse.51 Table 6 provides the take-home
message with regard to hGH.
CREATINE
Mechanism of Action
Creatine (or methyl guanidine-acetic acid) occurs nat-
urally in the skeletal muscles, heart, spermatozoa, brain,
11
Table 6. Take-home Message for Human Growth
Hormone
• In healthy young adults, exogenous human growth hor-
mone (hGH) provides no performance-enhancing
effects in the sense of increased strength or muscle mass.
• Exogenous hGH may increase lean body mass in healthy
young and elderly adults, but this increase is likely due
to an increase in noncontractile proteins.
• The evidence for an increase in bone mass in healthy
elderly subjects is equivocal.
• The abuse of hGH as an ergogenic substance has proven
potential for serious side effects and disease.
• For ergogenic purposes, hGH is a banned substance.
However, at this time no valid test exists to detect its
abuse.
seminal vesicles, macrophages, retinal photoreceptor
cells, kidney, liver, spleen, and lungs of vertebrates.64
About 95% of the body’s creatine pool is located in the
skeletal muscles. Approximately 70% of creatine is
stored in the muscles in a phosphorylated form, phos-
phocreatine (PC), and the remaining 30% is free crea-
tine.64,65
Creatine is constantly degraded to creatinine at a rate
of about 2 grams per day (for a 70-kilogram person),
which then diffuses through the muscle membrane and is
excreted through the kidneys in the urine. Creatine is
replenished by synthesis in the liver and by way of
dietary intake.64 Dietary sources of creatine include pork
(5 g/kg), beef (4.5 g/kg), and cold-water fish such as tuna,
salmon, and cod (1.5 to 2 g/kg). The denaturing process
that occurs with heating degrades some of the creatine,
so the content in uncooked food is somewhat higher. Vir-
tually no creatine is present in plant products, and veg-
ans have to rely solely on endogenous production, which
results in lower creatine muscle levels as compared to
those of nonvegans.65 Endogenous synthesis involves the
amino acids arginine, glycine, and methionine. The
enzyme glycine amidinotransferase catalyzes the first of
2 reactions, where an amidine group from arginine is
transferred to glycine to form ornithine guanidinoacetate.
In the second reaction, creatine and S-adenosylhomo-
cysteine are formed from guanidinoacetate and S-adeno-
sylmethionine with the enzyme guanidinoacetate
methyltransferase as a catalyst.64,65
The role of creatine in muscle is fourfold. It provides
an anaerobic mechanism for resynthesis of muscle
adenosine triphosphate (ATP) by way of a reaction that is
catalyzed by the enzyme creatine kinase: PC + adeno-
sine diphosphate (ADP) + H+ ↔ ATP + creatine. The
anaerobic nature of this resynthesis makes creatine a
major source of energy for high-intensity exercise; PC
use is maximal in the first second of this type of exertion
and decreases over 30 seconds.64 The creatine-PC system
also functions as a metabolic buffer by using H+ ions
during resynthesis of ATP. This ability to attenuate pH
changes in the muscle may delay onset of fatigue.64,65
Increased levels of ADP inhibit multiple enzymatic func-
tions involved in glycolysis and also the enzymes known
as ATPases; PC acts as a cellular buffer by attenuating the
ADP concentration changes.64 Finally, creatine is an
osmotically active substance, and the increased intracel-
lular water levels due to creatine supplementation have
been shown to stimulate muscle protein synthesis.64
Fast glycolytic muscle fibers contain about 30% more
creatine than slow oxidative fibers.64 Higher creatine
kinase activity in glycolytic fibers leads to a higher rate
of PC degradation. Phosphocreatine resynthesis occurs
in the muscle mitochondria. This resynthesis is slower in
glycolytic than in oxidative fibers due to lower intracel-
lular oxygen and higher H+ concentrations.64
Creatine supplements commercially available are cre-
atine monohydrate and creatine phosphate.65 Both appear
to be equally effective.65,66 Most research on creatine sup-
plementation has used short-term (≤14 days) supplemen-
tation with 20 to 30 grams of creatine monohydrate in 4
to 6 daily doses of 5 to 6 grams.64,65 This loading phase is
followed by a maintenance phase where 2 grams per day
is ingested.65 More prolonged low-dose supplementation
(3 grams per day over 4 weeks) has been shown to pro-
duce muscle creatine levels similar to these higher dose
regimens.64 Creatine uptake is enhanced with simultane-
ous ingestion of simple carbohydrates, probably by stim-
ulating an insulin-dependent creatine transmembrane
transport system.64,65 Muscle creatine levels return to nor-
mal in about 4 weeks after stopping supplementation.64,65
However, a case report on a competitive bodybuilder67
found that muscle PC levels decreased by only 22% over
30 days after an initial 45% increase after supplementa-
tion with 20 g/day for 5 days. In some individuals, the
washout period obviously may exceed 30 days, with an
accompanying persistent increase in body mass.
Effects on Performance
Based on the mechanism of action of creatine dis-
cussed above, one would expect to see performance-
enhancing effects of creatine supplementation mainly
with repeated high-intensity activities and body compo-
sition. Effects on single bouts of high-intensity exercise
and strength measures can also be hypothesized. Crea-
tine supplementation might have an effect on high-inten-
sity aerobic exercise.
Single bouts of high-intensity exercise use the crea-
tine-PC system as a major source of anaerobic energy.
However, research found no significant change in the
maximum number of repetitions with the preacher bench
curl in men (19 to 29 years) ingesting 20 g/day creatine
monohydrate or creatine phosphate for 3 days followed
by 10 g/day for the remainder of 6 weeks when com-
pared to a placebo.66 Research also showed no signifi-
cant benefit of 0.3 g/kg/day creatine monohydrate for 5
days followed by 0.03 g/kg/day for 32 days in men who
were recreational weightlifters (20 to 26 years) over
placebo on total lifting volume to failure at 80% of the
1-RM load for bench and incline leg press.68
12
In contrast to these negative outcomes, 2 studies have
found a significant increase (22.1%) in anaerobic work
capacity on the bicycle ergometer critical power test in
physically active women (age 22 ± 5years) compared to
a placebo after supplementation with 20 g/day for 5
days69 and in men (19.9 ± 1.6 years) after drinking 5.25
g/day of creatine monohydrate without (9.4%) or with 33
grams of dextrose (30.7%).70 A placebo group ingesting
35 g/day of dextrose had no significant changes.70 Sup-
plementation with 0.3 g/kg/day for 5 days and 2.25 g/day
for 9 days produced a significant improvement in the
100-meter sprint and a trend for improvement in the 50-
meter sprint in men and women who were Division III
NCAA swimmers (19.3 ± 0.2 years).71 On the other hand,
Dawson et al72 found no improvement in 50-meter and
100-meter sprint times for men and women who were
junior swimmers (16.4 ± 1.8 years) after supplementation
with 20 g/day for 5 days and 5 g/day for 22 days.
MacLaren64 concluded that creatine might improve sin-
gle bouts of intense exercise only when fatigue is present
due to previous activity.
The role of the creatine-PC system as a cellular and
metabolic buffer and its role in ATP resynthesis should
affect performance on repeated high-intensity activities.
However, one study73 noted no significant between-
group differences in peak and mean anaerobic power in
3 consecutive bouts of arm and leg Wingate tests in men
who were recreational athletes ingesting either 20 g/day
of creatine monohydrate or placebo for 6 days. This was
confirmed by another study74 that also found no signifi-
cant between-group differences on a repetitive leg
Wingate test in well-trained women subjects (27 ± 6
years) ingesting either 20 g/day of creatine monohydrate
or a placebo for 5 days. Edwards et al75 also found no sig-
nificant between-group differences in performance for
moderately active men (21.5 ± 3.6 years) ingesting either
a placebo or 20 g/day creatine monohydrate for 6 days
on a 20% incline treadmill test at 8 mph preceded by
four 15-second bouts of high-intensity running. Steven-
son and Dudley76 reported no significant between-group
differences on open chain knee extension 5-set perfor-
mance when comparing resistance-trained subjects
ingesting placebo or 20 g/day creatine monohydrate for
7 days. Delecluse et al77 found no effect of supplementa-
tion with 0.35 g/kg/day creatine monohydrate versus
placebo for 7 days in highly trained sprinters of both sex-
es on repeated 40-meter sprint times.
On the other hand, Warber et al78 noted a significant
increase in total repetitions on 5 sets of bench press at
70% of a 1-RM load in men (32 ± 5 years) ingesting 24
g/day of creatine monohydrate for 5 days when com-
pared to placebo. Earnest et al79 also reported a signifi-
cant effect for time to exhaustion on 2 consecutive about
90-second runs in well-trained men ingesting 20 g/day
for 4 days and 10 g/day for 6 days when compared to
placebo, mainly due to improvement in the second run.
Kirksey et al80 did find significant between-group differ-
ences in average peak power, peak power, total work,
and initial rate of power production in five 10-second
maximum cycle ergometer rides in collegiate track and
field athletes ingesting 0.3 g/kg/day for 6 weeks as com-
pared to placebo. Cottrell et al81 found that supplemen-
tation with 0.3 g/kg/day creatine monohydrate for 7 days
was effective in improving recovery from eight 15-sec-
ond cycling bouts in trained cyclists when the recovery
interval was less than 6 minutes long. MacLaren64 noted
that creatine supplementation has been shown to result
in a 4% to 10% improvement in performance with
repeated high-intensity exercises in the sense of cycling,
swimming, running, and vertical jumping with the great-
est effects in later bouts of exercise. Even studies show-
ing no significant improvement (possibly due to low
power) showed 2% to 4% improvements.64
Measures of strength could be considered single
bouts of high-intensity exercise. Some studies found no
effects of creatine supplementation. Syrotuik et al68 found
no significant change in 1-RM load for the bench and
incline leg press. Stevenson and Dudley76 found no sig-
nificant between-group difference on 1-RM for an open
chain knee extension exercise. Other studies have shown
significant effects for supplementation. Peeters et al66
found significant increases in the 1-RM load for the
bench press in the supplement versus placebo group.
Brenner et al82 reported significant between-group differ-
ences for the bench press 1-RM load, favoring the 20
g/day for 1 week followed by 2 g/day for 4 weeks sup-
plement situation over the placebo situation in female
collegiate lacrosse players. Larson-Meyer et al83 found
that in female collegiate soccer players, 15 g/day of cre-
atine monohydrate for 1 week followed by 5 g/day for 13
weeks resulted in a significantly higher 1-RM on bench
press and squat than ingesting a placebo.
Functional measures of strength have also been inves-
tigated. Haff et al84 found significant between-group dif-
ferences in jump-height performance with a counter-
movement jump when comparing a placebo to 0.3
g/kg/day creatine monohydrate for 6 weeks in male and
female track and field athletes. Watsford et al85 noted sig-
nificant increases in vertical jump and 20-centimeter
drop jump height after creatine supplementation with 20
g/day for 7 days and 10 g/day for 21 days in a group of
men (23.4 ± 4.9 years), with no change in the placebo
group. Kirksey et al80 found improved countermovement
vertical jump height and power index in collegiate track
and field athletes ingesting 0.3 g/kg/day for 6 weeks as
compared to placebo. MacLaren64 noted that reports of
the ergogenic effects on strength measures are mixed but
that on balance, the evidence for a positive effect is
greater than that for no effect.
Greater energy storage in the creatine-PC system
might be beneficial in high-intensity aerobic exercise.
Biwer et al86 provided male and female college soccer
players with a placebo or 0.3 g/kg/day of creatine for 6
days. Supplementation did not result in significant effects
during a submaximal treadmill run interspersed with
high-intensity intervals lasting more than 20 minutes.
13
MacLaren64 hypothesized a positive effect on aerobic
high-intensity activities from 4 to 12 minutes. No effect
has yet been found for longer-duration activities.
Creatine supplementation may affect body composi-
tion. Some of the studies reported above found no effect
of creatine supplementation on body weight,69–71,75
whereas others noted increased weight.78 Some reported
increased lean body mass,66,80,84 and 1 found no such
change.83 Some studies report a decrease in percentage
of body fat.78,82 Kutz and Gunter87 found significant
increases in body weight and body water content but not
in percent of body fat in men (22.9 ± 4.9 years) supple-
mented with 30 g/day for 2 weeks and 15 g/day for
another 2 weeks; they attributed the weight gain to
increased water retention. Powers et al88 found a signifi-
cant between-group difference with increased body mass
and total body water content in male and female resis-
tance-trained athletes ingesting 25 g/day for 7 days and 5
g/day for 21 days versus placebo. MacLaren64 reported
clear evidence for an increase in muscle mass in studies
where creatine supplementation was combined with
resistance training.
Medical Indications
Creatine has been used in the clinical medical setting
for inborn deficiencies of creatine metabolism, gyrate
atrophy of the choroids and retina, heart disease, neuro-
muscular disease, and recovery from orthopaedic injury
or surgery. Creatine may have a cytoprotective function
on cardiac muscle in patients with heart disease. It has
also been shown to positively affect blood triglyceride
and cholesterol levels.64
Some studies have investigated creatine supplementa-
tion in clinical situations. Jacobs et al89 found a signifi-
cant between-group difference in oxygen uptake and
tidal volume with arm ergometry in favor of patients with
complete C5 to C7 spinal cord injury ingesting 20 g/day
creatine monohydrate for 7 days when compared to
placebo. A 5-day protocol of 20 g/day creatine monohy-
drate did not produce greater total work production with
3 sets of 30 repetitions of isokinetic open chain knee
extensions over placebo in individuals with multiple
sclerosis.90 Creatine supplementation (10 g/day for 10
days presurgery and 5 g/day for 30 days postsurgery) did
not affect recovery from total knee arthroplasty.91 Crea-
tine has had positive effects in animal research into mus-
cular dystrophy and on strength in humans with mito-
chondrial cytopathies.92 Supplementation at 20 g/day for
5 days did not attenuate or enhance recovery from
eccentric-induced muscle injury.93
Side Effects
There are some case reports discussing adverse health
effects, including death due to renal dysfunction as a
result of combined high-dose creatine supplementation
and dehydration in athletes.64 However, prolonged (2 to
5 years) low-dose creatine use for clinical reasons has
not been documented to result in kidney dysfunction.
Taking low doses of creatine (3 to 5 g/day) during a main-
tenance phase together with sufficient volumes of fluid
should not pose a problem in an athlete with normal kid-
ney function.64 When considering creatine use, seeking
medical advice in case of renal disease is recommended.
Anecdotal reports of gastrointestinal upset, muscle
cramps, and muscle injuries have not been substantiated
by research; in fact, the incidence of gastrointestinal
upset was less in creatine users in a study comparing cre-
atine supplementation to a placebo.64 Gastrointestinal
upset has been associated with taking dosages above
recommended levels.65
Unnithan et al94 noted, based on their review of the
literature, that insufficient evidence existed to suggest the
use of creatine supplementation for children and adoles-
cents. Metzl et al12 noted that use among adolescents
should actively be discouraged until safety can be estab-
lished and suggest in general a nonpermissive attitude
from the medical community toward nutritional supple-
ment use in young athletes.
Testing and Regulation
Creatine is a natural component of food with a proven
significant effect on strength, power, speed, and lean
body mass. Determining the level of muscle creatine in
the context of drug testing would likely involve the need
for expensive (and invasive) muscle biopsy and magnet-
ic resonance imaging.64 An upper limit for maximum
total creatine content in muscle of 160 mmol/kg64 has
been suggested, but how does one determine whether
this is the result of a healthy diet or supplementation? If
any, above which level should an athlete be banned from
competition? In 1998, the IOC Medical Committee ruled
that creatine is a food and not a banned substance.65
Table 7 provides the take-home message for creatine
supplementation.
Table 7. Take-home Message for Creatine
• Creatine supplementation has a proven significant per-
formance-enhancing effect on strength, power, speed,
and lean body mass.
• With the possible exception of aggravating a pre-existing
renal dysfunction with creatine supplementation in
combination with insufficient hydration, the use of cre-
atine does not seem to produce clinically significant
side effects.
• Insufficient evidence exists with regard to efficacy and
safety of creatine use in children and adolescents.
• Creatine is not considered a banned substance.
BETA-HYDROXY-BETA-METHYLBUTYRATE
Mechanism of Action
Beta-hydroxy-β-methylbutyrate (HMB) is a metabolite
of the branched-chain amino acid leucine.95,96 Beta-
hydroxy-β-methylbutyrate concentrations in the body are
maintained both by dietary intake (eg, by eating catfish
and grapefruit) and by endogenous production.97 The first
14
step in the endogenous production of HMB is the
transamination of leucine to α-ketoisocaproate. The
cytosolic enzyme α-ketoisocaproate-dioxygenase then
catalyzes the production of HMB from α-ketoiso-
caproate. Normal plasma concentrations of HMB vary
from 1 to 4 mmol/L but can increase fivefold to tenfold
after ingestion of leucine.95 Beta-hydroxy-β-methylbu-
tyrate production in the body seems mainly controlled by
enzyme and α-ketoisocaproate concentrations; on aver-
age, a 70-kilogram person will produce 0.2 to 0.4 grams
of HMB per day.98 Normally, 5% of leucine oxidation
proceeds via the pathway described above.95 However,
exercise affects leucine metabolism, with oxidation
increasing by a factor of up to 4.8 as a result.96
The mechanism by which HMB brings about its doc-
umented positive effects is not totally clear. The hypoth-
esis that HMB works through a testosterone-mediated
pathway was discredited by Slater et al,99 who found no
change in the testosterone to epitestosterone ratio in
healthy men after ingesting 3 grams of HMB per day for
2 weeks. The role of HMB in maintaining muscle mem-
brane integrity is more evident. Beta-hydroxy-β-methyl-
butyrate is converted in the cytosol and the liver to β-
hydroxy-β-methylglutarate-Co-A (HMG-CoA), which is
then used for cholesterol synthesis. Stressed or damaged
cells may be unable to produce HMG-CoA in sufficient
quantity to support adequate cholesterol production.95
An increase in cytosolic cholesterol production as a
result of an increase in HMB concentrations may be used
to maintain muscle cell membrane integrity and thus
prevent muscle damage. It may also be used to regener-
ate damaged muscle membranes, thus speeding recov-
ery.100 Other less substantiated hypotheses as to the
mechanism of action of HMB include:
• Stimulation of cellular proteinosis with decreased
recovery time due to increased collagen and con-
nective tissue synthesis.97
• Regulation of enzymes responsible for muscle break-
down.97
• Stimulation of liver metabolism, with increases in
the rate in the Cori cycle resulting in a more effective
conversion of lactate to glucose.96
• Stimulation of mitochondrial and cellular protein
concentration with a subsequent increase in cellular
oxidative capacity and decreased production of lac-
tate.96
• Increased muscle buffer capacity for H+ ions as a
result of the increase in muscle protein content96
Beta-hydroxy-β-methylbutyrate supplementation gen-
erally comes in the form of orally ingested capsules.
Most research has studied a daily dose of 3 grams of
HMB per day.
Effects on Performance
Based on its hypothesized and more substantiated
mechanisms of action, HMB supplementation might be
expected to have a direct positive influence on high-
intensity aerobic exercise by way of its possible effect on
lactate production and metabolism and on markers of
muscle damage as a result of exercise by way of its effect
on muscle membrane integrity. Indirectly, HMB supple-
mentation might positively affect measures of both
strength and endurance and body composition by
decreasing recovery time after strenuous exercise.
Nissen et al98 studied the effect of simultaneous resis-
tance training and HMB supplementation in 2 groups.
One portion of the study compared men (19 to 29 years)
taking 0, 1.5, or 3 grams of HMB per day for 3 weeks
while engaging in a resistance-training program 3 times
per week. This study found a significant between-group
difference favoring the HMB-supplemented groups, with
lower plasma creatine phosphokinase levels indicative of
muscle damage, decreased proteolysis as measured by
urinary 3-methylhistidine levels, and a higher volume
measure of total weight lifted. The second portion of the
study compared men (19 to 22 years) who did resistance
training 6 days per week for 7 weeks while ingesting
either 0 or 3 grams of HMB per day and found a signifi-
cant between-group difference with an increase in fat-
free mass in the HMB group.
Kreider et al101 supplemented resistance-trained ath-
letes simultaneously engaged in a resistance-training
program with 0, 3, or 6 grams of HMB per day for 28
days. The study found no significant between-group dif-
ferences for fat-free mass, bone-free mass, percentage of
body fat, and 1-RM load on the bench press or leg press.
Knitter et al100 compared 6 weeks of ingestion of 3
grams of HMB per day to placebo in experienced run-
ners of both sexes. Despite similar performance on a 20-
kilometer collegiate cross-country run, they found a sig-
nificant between-group difference in creatine phosphok-
inase and lactate dehydrogenase postrun blood-level
responses, indicating a lesser degree of muscle damage
in the supplemented group.
Panton et al102 compared placebo to supplementation
with 3 grams of HMB per day in men and women (20 to
40 years) engaged in a resistance-training program. The
study noted a trend for lower plasma creatine phosphok-
inase levels in the supplemented group and a significant
increase in a volume measure of upper body strength
favoring the HMB-supplemented group. There was also a
between-group trend for increased fat-free weight and
decreased percentage of body fat (P = .08) in the HMB
group.
Vukovich and Dreifort96 compared ingestion of 3
grams of HMB per day for 2 weeks to ingestion of 3
grams per day of leucine or placebo in competitive mas-
ters-level cyclists (34.2 ± 2.6 years). They found a signif-
icant between-group difference in the onset of blood lac-
tate accumulation (defined as the oxygen consumption
per unit time [VO2] at levels of blood lactate of 2 mmol/L)
favoring the HMB-supplemented group.
Ransone et al97 compared 4 weeks of supplementa-
tion with 3 grams of HMB per day to placebo in NCAA
15
Division I football players involved in a strenuous exer-
cise program. They found no significant between-group
differences on the predicted 1-RM load for the bench
press, squat, and power clean or with regard to body
weight or percentage of body fat. The authors hypothe-
sized that the effects of supplementation might have
been decreased due to the state of overtraining associat-
ed with the high volume of the exercise program.
In summary, the research reviewed here seems to sup-
port the hypothesized positive effect of HMB supple-
mentation on preventing muscle damage and delaying
the onset of blood lactate accumulation. Effects on mea-
sures of strength and body composition are equivocal but
seem to indicate a positive ergogenic effect. No data
indicate a positive effect on aerobic endurance.
Medical Indications
Lynch92 noted that HMB supplementation in combi-
nation with supplementation with the amino acids L-glu-
tamine and L-arginine has been shown to be effective in
slowing the course of muscle wasting in patients with
acquired immunodeficiency syndrome. However, he
also reported that further study is needed to determine
the efficacy of HMB supplementation as a medical inter-
vention in patients with neuromuscular disorders.92
Side Effects
Nissen et al95 performed a systematic review with
regard to safety of HMB supplementation. The reviewed
studies researched the effects of ingestion of 3 grams of
HMB per day for a period varying from 3 to 8 weeks.
Subjects included men and women, both young and old,
who took HMB with or without participating in a struc-
tured exercise program. Adverse effects were monitored
by way of hematological work-up, a test of mood state,
and an adverse-effects questionnaire. The review showed
no adverse effects on any marker of tissue health or func-
tion. Ingestion of HMB resulted in a net decrease as com-
pared to the placebo group in total cholesterol, low-den-
sity lipoprotein cholesterol, and systolic blood pressure.
There was also a significant decrease in 1 indicator of
negative mood with HMB supplementation. The HMB
group showed a trend to reporting less loss of appetite
and less diarrhea than the placebo group. A higher report
of onset of stiff joints in the HMB group was dismissed as
an artifact of pretest between-group differences. The
authors concluded that HMB was well-tolerated and safe
for use as an ergogenic supplement in humans.95
Testing and Regulation
Beta-hydroxy-β-methylbutyrate is a natural compo-
nent of food with a proven positive effect on blood mark-
ers of muscle damage and on anaerobic endurance. It is
available in over-the-counter nutritional supplements
and to date has not been banned by any sporting organi-
zation.103 Table 8 provides the take-home message on
HMB. A word of caution to the novice (especially the
Table 8. Take-home Message for β-hydroxy-β-methylbu-
tyrate
• β-hydroxy-β-methylbutyrate (HMB) supplementation
has a proven effect on markers of muscle damage and
anaerobic performance with equivocal effects on
strength and body composition.
• The literature reviewed indicates no negative side effects
but rather a potentially cardioprotective effect from
HMB supplementation.
• HMB has not been banned by any sporting organization.
female athlete thinking of using HMB for ergogenic pur-
poses) to avoid confusion between HMB and gamma-
hydroxybutyric acid, abbreviated to GHB; this sub-
stance, which was originally developed as an anesthetic
agent has been touted as an ergogenic substance and
information on its manufacture is still available on the
Internet, but it is now classified as a federal Schedule I
controlled substance in the United States due to its doc-
umented use as a date rape drug.104 The importance of
knowing one’s abbreviations is evident in this case.
ALCOHOL
Mechanism of Action
Ethanol or ethyl alcohol is obtained by fermenting
sugar. It is part of a group of chemicals called alcohols.
Unlike most alcohols, ethanol (further called alcohol) is
nontoxic except in large or chronic doses. Small
amounts of alcohol (up to 7.5 milligrams total) are pro-
duced endogenously from bacterial fermentation in the
gut and the action of alcohol dehydrogenase on
acetaldehyde derived from pyruvate. Most alcohol is, of
course, of exogenous origin.105
Alcohol is absorbed unaltered after ingestion in small
amounts in the mouth, more in the stomach, but mostly
in the small intestine.105,106 The rate of absorption depends
on the type of alcoholic beverage, the speed of con-
sumption, the concentration of alcohol and other chem-
icals in the beverage, gastric mobility, body weight,
stomach contents, and factors influencing gastric empty-
ing (beverage carbonation, emotional state, and condi-
tion of the stomach tissues).106 Absorption is quicker
when alcohol is drunk on an empty stomach and when
the beverage is carbonated and has high alcohol content.
Absorption is slower with intense mental concentration,
lower body temperature, and when exercising. Blood
alcohol levels peak about 45 minutes after ingestion of a
single drink. This peak is delayed by 15 minutes when
strenuous exercise precedes the drink.105
Alcohol quickly penetrates all biological membranes
including the blood-brain barrier, acting as an almost
instantaneous central nervous system depressant.
Although soluble in fat as well as water, alcohol does not
distribute significantly into fatty tissue. This explains why
similar quantities affect people with higher fat-free mass
less than people with a higher proportion of body fat;
women with, on average, a higher proportion of body fat
are more affected by alcohol than equal-weight men.106
16
Alcohol is partly eliminated through breath, urine,
and sweat (2% to 10%); higher excretion rates occur
with higher temperatures and higher blood alcohol lev-
els. However, the liver metabolizes the majority of alco-
hol (90% to 98%) at a constant rate of 100 mg/kg/h.105,106
The hepatic enzyme alcohol dehydrogenase converts
alcohol to acetaldehyde. In turn, this substance is con-
verted by the enzyme aldehyde dehydrogenase to acetic
acid. Some 75% of ingested alcohol is released into the
circulation as acetic acid and metabolized in the Krebs
cycle to carbon dioxide and water. Acetic acid is also
activated to acetyl coenzyme A, which is then further
metabolized to fatty acids, ketones, amino acids, and
steroid compounds.105 The speed of hepatic metabolism
is determined by the function of liver enzyme systems.
Age, menstrual cycle, heredity, race, liver disease, and
experience with alcohol and other drugs may affect the
function of these enzyme systems and thus alcohol
metabolism and clearance.106 Alcohol is not metabolized
by muscle, making it impossible to exercise oneself to
sobriety.105
Alcohol causes vasodilation of superficial vessels:
using alcohol to warm up in cold environmental circum-
stances may thus lead to heat loss and hypothermia.
Alcohol is also a diuretic and may negatively affect elec-
trolyte balance needed for optimal performance. The
anticoagulant properties of alcohol may be a risk factor
when combining alcohol use with contact sports. Alco-
hol also stimulates gastric secretion and appetite.106
The main effects of alcohol are mediated by its
actions on the central nervous system. Ingesting alcohol
lowers central calcium levels. This decreases the perme-
ability of the axonal membranes to Na+ and K+, gener-
ally slowing nerve conduction. Alcohol also blocks
release and synthesis of acetylcholine. Decreased activi-
ty in the ascending acetylcholinergic reticular pathway
decreases cortical arousal and thereby lowers concentra-
tion, attention, skilled performance, and eventually
short-term memory. Alcohol also inhibits tryptophan
hydroxylase. This enzyme is responsible for the synthesis
of serotonin. Decreased activity in serotonergic pathways
lowers the experience of anxiety in stressful situations.
The initial euphoric state when alcohol levels are
increasing followed by mood reversal when alcohol lev-
els drop again is related to the effect of alcohol on nora-
drenergic pathways. Alcohol also stimulates the brain to
release dopamine, which improves mood, decreases
nociperception, and eventually causes a mild cerebellar
ataxia. In addition, alcohol stimulates glucose utilization
in the brain, and the subsequent drop in brain glucose
levels produces mental fatigue.105
Alcohol has been part of human culture at least since
8000 BC. Alcoholic beverages are produced in the form
of beer (4% alcohol by volume), wines (12% to 20%),
liqueurs (22% to 50%), and distilled spirits (40% to
50%). A “standard” drink usually contains 16 grams of
alcohol.106
Effects on Performance
Considering the effects of alcohol, it is unlikely that
this substance has an ergogenic effect on measures of
strength and endurance. It does, however, have potential
as a performance-enhancing anxiolytic in highly stressful
athletic events.
In regard to the effects of alcohol on endurance, Borg
et al107 studied the effects of 1 g/kg alcohol in fit men on
performance during a progressive bicycle ergometer
exercise protocol. Each subject served as his own con-
trol. Alcohol caused a significant increase in heart rate at
an intensity of 50 W and 100 W (8 and 10 beats per
minute, respectively). Thereafter, heart rate, systolic
blood pressure, blood lactate, or rating of perceived
exertion were not significantly affected by alcohol. The
authors concluded that a moderate dose of alcohol did
not affect exercise capacity. Blomqvist et al108 had
healthy men ingest 150 milliliters of alcohol. At submax-
imal intensities, increased VO2 and increased heart rate
resulted in increased cardiac output at equal workloads
when compared to the no-alcohol test. Respiratory func-
tion was not altered by alcohol use and there were no
changes at maximal intensity.
The anxiolytic effects of alcohol may be beneficial to
the performance of aiming sports such as darts, billiards,
pistol shooting, archery, and snooker. Alcohol use in
small doses is a common component of archery and
darts. Reilly and Halliday109 tested subjects under 4 dif-
ferent conditions: sober, placebo, and 0.02% and 0.05%
blood alcohol level. They found no significant effects on
measures of isometric strength and muscular endurance
but did find significantly dose-dependent slowed reac-
tion time and impaired steadiness with alcohol ingestion.
However, electromyographic measures indicated
reduced muscle tremor with exercise. A similar study on
dart throwing showed negative effects of the lighter alco-
hol dose on eye-hand coordination but increased bal-
ance and higher scores.110 A 0.05% blood alcohol level
led to deterioration of performance on all tasks mea-
sured.
In summary, moderate doses of alcohol do not seem
to have a negative effect on endurance activities, but the
lack of any ergogenic effect makes alcohol an unlikely
choice for a performance-enhancing substance. Small
amounts of alcohol may improve performance in some
aiming sports.
Medical Indications
Alcohol has been used in medicine as an antiseptic, an
anesthetic, and a sedative. It is still used for sedation in
liquid medications (eg, cough syrups).106 The use of alco-
hol as an anesthetic was stopped when the medical com-
munity realized that it was too dangerous to use in the
large quantities needed for that purpose.105 Another med-
ical use is during detoxification in a person with alcohol
dependence.106 Cross-sectional studies have shown an
association of light drinking with lower blood pressure, an
increase in high-density lipoprotein cholesterol, and a
17
lower incidence of coronary artery disease and myocar-
dial infarction.105 However, methodological issues make
the interpretation of these studies problematic.106
Side Effects
Ingestion of alcohol results in both acute and chronic
effects. Table 9 summarizes the acute effects of various
blood alcohol levels.106 Whereas the effects of lower
blood levels may be desirable at times, the effects of the
higher levels clearly are not. Alcohol overdose occurs
when excessive amounts of alcohol are ingested in a very
short time and may result in death. Usually loss of con-
sciousness occurs before overdose, but college and ado-
lescent drinking games every year still result in multiple
deaths.106 Relevant to the athletic setting is that postexer-
cise alcohol consumption perturbs blood hemostasis and
may increase risk of thrombosis.111 Also relevant is the
deleterious effects that the nausea, vomiting, headache,
and thirst associated with a hangover can have on athlet-
ic performance. Even nondependent binge drinkers with-
out a history of heart disease run the risk of “holiday heart
syndrome,” experiencing depressed cardiac function and
arrhythmia.106
Table 9. Acute Effects of Different Levels of Alcohol
Ingestion*
Blood Alcohol Effects
Level
0.02 Sense of warmth and well-being in light
and moderate drinkers.
0.04 Slight impairment of motor skills. Feeling
relaxed, energetic, and happy.
0.05 Lightheadedness and lowered inhibitions.
Slightly affected coordination.
0.06 Ability to make decisions regarding
personal abilities affected.
0.08 Increased reaction time and impaired
coordination. Heavy pulse and slowed
respiration. May have numbness in lips,
cheeks, and extremities.
0.10 Staggering, fuzzy speech. Judgment and
memory affected. Legally drunk in most
states.
0.15 Definite impairment of balance and
movement.
0.20 Slurred speech, double vision, and diffi-
culty standing and walking.
0.30 Confusion and stupor. May lose
consciousness.
0.40 Usually unconscious. Skin is sweaty and
clammy.
0.45 Circulation and respiration are depressed
or stopped.
0.50 Near death.
*Adapted from Stainback and Jansevics-Cohen.106
 Chronic alcohol abuse results in adverse health
effects in multiple body systems. Probably the most
telling outcome measure is that life expectancy of an
alcoholic is 15 years less than that of a nondependent
individual. Mortality rates among alcoholics are 2.5 to
3.3 times higher due to accidents, suicide, homicide,
and other health issues.106 Alcoholic liver disease is the
most common cause of liver disease in the Western
world. Of all deaths attributed to liver disease, 75% are
related to liver cirrhosis. In the United States, cirrhosis is
the fourth leading cause of death in people aged 25 to
64.112 Cancer also occurs more frequently in cirrhotic liv-
ers. Women who drink alcohol regularly are more sus-
ceptible to breast cancer. Years of alcohol abuse can
cause cardiomyopathy, generalized skeletal myopathy,
pancreatitis, and cancer of the larynx and pharynx. Alco-
hol dependency can result in alcoholic psychosis.105
Alcoholism can also lead to encephalopathy and cere-
bellar degeneration.113
Alcohol easily crosses the placenta, and even 1 to 2
drinks a day can result in fetal growth retardation. More
than 4 to 5 drinks a day during pregnancy may result in
fetal alcohol syndrome with mental retardation, micro-
cephaly, growth deficiencies, and facial abnormalities.106
Testing and Regulation
In most countries, law restricts the use of alcohol by
minors. In some countries in the Middle East, there are
strict religious edicts against the use of alcohol.106 Alco-
hol is prohibited in several sports (eg, modern pen-
tathlon, fencing, and shooting).105 The NCAA has banned
alcohol from rifle-shooting competitions.106 In other
sports such as darts, snooker, and billiards, the use of
alcohol is still very much an accepted part of competi-
tion.105 Table 10 contains the take-home message for
alcohol.
Table 10. Take-home Message for Alcohol
• Alcohol has no proven ergogenic properties in the sense
of increased strength or endurance.
• In low doses, it may confer an advantage in aiming
sports.
• Alcohol in large or chronic doses is toxic with adverse
health effects in multiple organ systems. Law and reli-
gion limit or prohibit the use of alcohol.
• Alcohol is prohibited in modern pentathlon, shooting,
and fencing.
CAFFEINE
Mechanism of Action
Caffeine (1,3,7-trimethylxanthine) is a member of the
methylxantine group, which also includes theophylline,
paraxanthine, and theobromine. Caffeine occurs natural-
ly in more than 60 plants, including coffee, tea, cocoa,
and guarana.114,115 Caffeine content of foods and bever-
ages depends to a large extent on processing method; fil-
18
tered coffee contains more caffeine than percolated cof-
fee and longer brewing increases caffeine content of tea.
Caffeine is also added to many soft drinks and is avail-
able in over-the-counter cold and headache medica-
tions.114
Orally administered caffeine is absorbed by nearly
100%. It can be detected in the blood within 5 minutes
from ingestion. Caffeine occurs in the blood mainly
unbound; only 15% to 17% binds to plasma proteins.
Peak plasma concentrations usually occur after 30 to 60
minutes with a range of 15 to 20 minutes due to
interindividual variations in gastric emptying. Caffeine is
water and lipid soluble and, therefore, diffuses rapidly
from the plasma into all body tissues including the
brain.114 Normally, the half-life of caffeine in the body is
3 to 6 hours.114,115 However, clearance is nonlinear so that
higher doses are metabolized more slowly.115 Caffeine is
broken down in the liver by the hepatic cytochrome
P450 1A2 enzyme to theophylline (4%), theobromine
(12%), and paraxanthine (84%).114,115 These metabolites
have potencies similar to caffeine and contribute to the
systemic effects.115 The P450 enzyme system also metab-
olizes selective serotonin selective reuptake inhibitors
and the steroids in oral contraceptives. The use of oral
contraceptive agents, selective serotonin reuptake
inhibitor antidepressants, and alcohol reduces caffeine
metabolism, thus raising plasma levels.114 High-intensity
exercise slows elimination of caffeine, more markedly in
women than in men.114 Cigarette smoking stimulates
P450 activity and thereby enhances clearance of caf-
feine.115
Multiple mechanisms have been proposed to explain
the ergogenic effects of caffeine.115,116 Caffeine inhibits the
5’-nucleotidase enzymes, and the resultant decreased
conversion of adenosinemonophosphate (AMP) to
adenosine may play a role in protecting exercising tissues
from ischaemia.114 In vitro, caffeine also enhances calci-
um release from the sarcoplasmic reticulum. However,
similar concentrations in vivo would be toxic to humans,
making this mechanism unlikely.115,116 A third mechanism
involves the caffeine-mediated inhibition of the cyclic
nucleotide phosphodiesterase enzymes. Inhibition of
these enzymes increases the activity of intracellular sec-
ond messengers, including cyclic-AMP.114,115 Increased
cyclic-AMP levels stimulate release of catecholamines
(epinephrine and norepinephrine). The “glycogen-spar-
ing” hypothesis suggests that these increased cate-
cholamine levels may stimulate lipolysis, and promoting
the release of free fatty acids may save glycogen stores for
later use during prolonged exercise, thus delaying
fatigue.115–118 Research shows inconsistent support for this
mechanism, with reports of glycogen sparing only in the
first 15 minutes of exercise at about 80% VO2max.119 The
majority of the effects of caffeine seem mediated by a
competitive antagonism for adenosine receptors. Activa-
tion of these receptors depresses neurotransmission, epi-
nephrine and dopamine release, and lipolysis, and
increases glycogenolysis and muscular glucose
uptake.114,115 Stimulation of A2 receptors causes peripheral
and cerebral vasodilation, and A3 receptor stimulation
inhibits eosinophil migration.114 Even at physiologic lev-
els, caffeine, theophylline, and theobromine are strong
competitive antagonists of the adenosine A1 and A2 recep-
tors; caffeine is also a weak antagonist of the A3 receptor.
Chronic caffeine ingestion increases the number of
adenosine receptors, thus providing a plausible explana-
tion for the observed tolerance to caffeine.115 Table 11
summarizes the widespread systemic effects of caffeine.114
Table 11. Effects of Caffeine
• Increased gastric acid and pepsin secretion.
• Increased heart rate, stroke volume, cardiac output, and
resting blood pressure.
• Increased lipolysis.
• Increased skeletal muscle contractility.
• Increased oxygen consumption and metabolic rate.
• Increased urinary output.
• Potentiation of the antinociceptive action of non-
steroidal anti-inflammatory drugs.
• Mild independent antinociceptive action.
• Increased vigilance and attention.
• Decreased deterioration of cognitive performance with
fatigue.
• Effects on mood ranging from increased vigor and
euphoria to dysphoria and anxiety.
Caffeine for ergogenic purposes is sold in the form of
tablets, as a powder contained in gelatin capsules, and as
suppositories.114,119,120 Athletes have also used caffeinated
beverages as a source of caffeine. Caffeine is absorbed
more slowly from soft drinks than it is from tea or coffee.
Pure caffeine may have greater ergogenic effects than
equivalent amounts of caffeine from coffee, which may
also contain antiergogenic compounds.114,119
Effects on Performance
It is difficult to hypothesize as to the expected
ergogenic effects of caffeine due to the multiple periph-
eral and central mechanisms proposed for its action. The
direct effect on muscle calcium kinetics would indicate
an effect on strength and muscular endurance. The
mechanisms of action involving alterations in substrate
utilization and central excitation would seem to indicate
a possible effect on prolonged aerobic activities.
As for strength and endurance effects, Jacobson and
Edwards121 administered placebo, 300 milligrams, or 600
milligrams of caffeine to men and women with similar caf-
feine-consumption histories. They found no significant
effects for peak torque and muscular endurance on isoki-
netic tests of the knee flexors and extensor muscles. Bond
et al122 administered 5 mg/kg of caffeine or placebo to
male collegiate track athletes and found no significant
19
effects on peak torque, power, and endurance with isoki-
netic knee flexion and extension. Plaskett and Cafarelli117
administered 6 mg/kg of caffeine or a placebo to men
(22.6 ± 0.6 years) not using caffeine. They found a signif-
icant increase in endurance measures (17 ± 5.25%) dur-
ing repeated isometric contractions at 50% of maximum
voluntary capacity and a significant increase in maximum
voluntary capacity (5 ± 2%) in the caffeine condition.
However, these changes were not the result of simultane-
ously monitored contractile characteristics. Rather, the
authors showed a decrease in force sensation with caf-
feine, and they attributed the observed ergogenic effects
to alterations in muscle sensory processes due to caffeine
ingestion. Greer et al123 administered placebo or 6 mg/kg
caffeine to recreationally active men (29.1 ± 2.7 years)
and found no effect on peak and average power output
during 4 consecutive 30-second Wingate sprint cycling
tests.
As for effects on aerobic endurance, Hunter et al124
administered 6 mg/kg of caffeine and 0.33 mg/kg top-up
doses every 15 minutes or placebo to trained male
cyclists during a 100-kilometer trial ride with several
high-intensity intervals. They found no significant
between-group differences in total time, interval perfor-
mance, average power, and electromyographic measures.
Cole et al125 provided 6 mg/kg of caffeine or placebo to 10
subjects. They noted a significant increase in average total
work for the caffeine group only on a 30-minute cycling
test involving periods with ratings of perceived exertion
varying from 9 to 15 on the Borg rating of perceived exer-
tion scale. Birnbaum and Herbst120 administered 7 mg/kg
of caffeine or placebo to male and female collegiate
cross-country runners. Subsequent treadmill runs at 70%
VO2max resulted in significant between-group differences
in tidal volume, alveolar ventilation, and rating of per-
ceived exertion favoring the caffeine group. Bell and
McLellan126 had caffeine users and nonusers (32 ± 7
years) ingest 5 mg/kg of caffeine or placebo and then
measured time to exhaustion 1, 3, and 6 hours after
ingestion on a bicycle test at 80% VO2max. They found
significant between-group differences favoring the caf-
feine group at all times for nonusers and at 1 and 3 hours
for caffeine users and noted that the ergogenic effects of
caffeine were greater in the absence of habituation.
In summary, caffeine may have an effect on maximal
isometric force and submaximal isometric endurance but
seems to lack an effect on dynamic measures of strength
and muscular endurance. Research supports an
ergogenic effect on moderate-intensity to high-intensity
activities lasting 90 to 120 minutes.115 These effects
appear to be smaller in habituated caffeine users, but
responses are again potentiated after 4 days of caffeine
withdrawal.117 The evidence for caffeine as an ergogenic
substance in female athletes is limited.119
Medical Indications
The potentiation of the analgesic effect of non-
steroidal anti-inflammatory drugs in combination with
the independent antinociceptive properties of caffeine
has led to the inclusion of caffeine in a number of phar-
macological preparations, including over-the counter
headache and cold medications.114,116 Birnbaum and
Herbst120 suggested a possible role for caffeine in athletes
with exercise-induced asthma.
Side Effects
Caffeine results in mood effects generally perceived
as positive with doses of up to 100 to 200 milligrams.
Doses greater than 400 milligrams cause lowered mood
and anxiety. Mild side effects of caffeine use can include
nervousness, irritability, insomnia, and gastrointestinal
upset. Severe adverse effects include peptic ulcers, delir-
ium, coma, and seizures. Doses greater than 200 mg/kg
have been associated with supraventricular arrhythmias.
The main chronic side effect of caffeine use is elevation
of serum cholesterol levels. Caffeine intoxication may
simulate an anxiety attack with nausea, insomnia, ner-
vousness, and jitteriness. Caffeinism is a medical syn-
drome involving anxiety, mood changes, sleep disrup-
tion, psychophysiological changes, and withdrawal
symptoms. Caffeine withdrawal can result in headaches,
muscular twitching, decreased mood states, insomnia,
and irritability.114,127
Testing and Regulation
In the context of athletic competition, caffeine is a
controlled and restricted substance. The IOC considers
postcompetition urinary levels exceeding 12 mg/mL
indicative of illegal use of this substance for ergogenic
purposes.117,118 The NCAA uses an upper limit of 15
mg/mL. Generally, ingestion of 9 mg/kg causes the ath-
lete to achieve urinary levels of 12 mg/mL.118 Caffeine is
regulated under the Dietary Supplement Health and Edu-
cation Act and as such content and dose of caffeine sup-
plements is not evaluated or certified.115 Table 12 con-
tains the take-home message for caffeine.
Table 12. Take-home Message for Caffeine
• Caffeine has a proven ergogenic effect on activities
requiring aerobic endurance.
• Caffeine may have some effect on muscular endurance
during submaximal tasks.
• At ergogenic doses, the potential for serious adverse
effects is small.
• Insufficient evidence exists on the ergogenic effects in
women athletes.
• Caffeine is a restricted substance in athletic competition,
but it has proven ergogenic effects well below legal lim-
its.
AMPHETAMINES
Mechanism of Action
Amphetamines are a group of structurally related
drugs also called phenethylamines that includes dex-
troamphetamine, methamphetamine, phenmetrazine,
20
and methylphenidate.114,128 Methylphenidate is probably
best known as the drug Ritalin, which is used in the treat-
ment of attention-deficit/hyperactivity disorder.128 Meth-
amphetamine and its derivative methamphetamine
hydrochloride are illicit street drugs with high addiction
and abuse potential.129 Amphetamine or phenyl iso-
propylamine was first synthesized in 1887 and first intro-
duced as a drug by the name of Benzedrine in 1920.114,128
Amphetamines are mainly absorbed from the small
intestine and reach peak plasma levels 1 to 2 hours after
administration. Complete absorption occurs within 2.5
to 4 hours and is increased by simultaneous intake of
food.114 Some 20% binds to plasma proteins.128 Amphet-
amines are cleared from the body by renal filtration with
an elimination half-life of 10 to 13 hours.114,128 Most
amphetamine is excreted unaltered, but a small portion
is excreted in the form of its main metabolites, p-hydrox-
yephedrine and p-hydroxyamphetamine. These metabo-
lites have a pharmacological action similar to that of the
parent substance.114
There are multiple suggested mechanisms of action
for amphetamines. Amphetamines may increase presy-
naptic release of the neurotransmitters norepinephrine,
dopamine, and serotonin. Amphetamine-mediated inhi-
bition of monoamine oxidase activity decreases the
breakdown of serotonin and dopamine. Amphetamines
also decrease dopamine and norepinephrine reup-
take.114,128,130–132 Increased release and decreased reuptake
and metabolism result in increased synaptic neurotrans-
mitter concentrations with resultant increased local
nerve-impulse transmission. George114 also noted a pos-
sible direct effect on the neurotransmitter receptors.
The main effect of amphetamines seems mediated by
activation of noradrenergic pathways.114 Amphetamines
have an agonist activity on α1, α2, and, to a lesser extent,
β1 noradrenergic receptors.130 Stimulation of α1-receptors
on vascular smooth muscle produces muscle contraction
and resultant vasoconstriction. Other effects have been
identified on spinal cord interneurons whose disinhibi-
tion produces increased motor neuron excitability. Stim-
ulation of the β1-receptors, located mostly on the
myocardium, results in increased heart rate and cardiac
output.130 Overall effects are summarized as increasing
blood pressure and heart rate, as well as glycogen and
fatty acid metabolism.133,134
Amphetamines can be taken orally as a tablet,
inhaled as a nasal spray, or injected.114,128 Methampheta-
mine hydrochloride crystals are inhaled by smoking,
albeit hardly for ergogenic reasons.129
Effects on Performance
Amphetamines are commonly called uppers because
they produce euphoria, false self-confidence, and self-
assertion or aggression in addition to masking fatigue.134–136
The decreased sense of fatigue and increased self-confi-
dence are among the effects that have prompted abuse by
athletes, even to the point of playing with an injury.132
Other athletes such as ballet dancers, wrestlers, and gym-
nasts have used the appetite-suppressant dopaminergic
effects to maintain a low body weight.136 Amphetamines
do not increase intellectual performance unless fatigue
and boredom have degraded performance. Ampheta-
mines do increase short-term learning of new tasks.
Amphetamines also cause a small distortion of time per-
ception that may interfere with motor planning.114
Earliest studies produced conflicting results regarding
amphetamine effects on aerobic and anaerobic perfor-
mance. A landmark double-blind comparison of weight-
lifting performance, swimming, and running demonstrat-
ed performance improvement in all 3 areas, with the
largest increase of 3% to 4% in weightlifting.137 Swim-
ming performance improved the least. Another study138
prior to 1970 measured amphetamine effects on swim-
ming and running, and contradicted those results with
findings of either neutral or negative results in untrained
individuals. Similar studies on aerobic performance were
repeated recently and the effects were not found, possi-
bly because the Controlled Substances Act of 1970 made
amphetamines illegal for ergogenic purposes.139
Later work concluded that subjects given ampheta-
mines were able to maintain exercise longer under
anaerobic conditions.140 Significant improvements were
noted in strength, acceleration, and aerobic power.
Notable is the finding that lactic acid and exercise
endurance increased during maximal exercise while VO2
was not affected, supporting the premise that ampheta-
mines mask, rather than delay, fatigue.140
In summary, the current view is that amphetamine use
does not enhance athletic performance directly; howev-
er, a 1% to 2% increase in short-term power activities
may be produced due to enhanced confidence and
aggression.132
Medical Indications
Amphetamines were originally used as nasal decon-
gestants and later as stimulants to increase alertness in air
force servicemen during prolonged missions.114,128 Until
recently, amphetamines were prescribed to treat nar-
colepsy, but now their only medical use is in the treat-
ment of attention-deficit/hyperactivity disorder.114 Med-
ical use of amphetamines for weight loss is still approved
in some countries but is discouraged in the United States
due to the high abuse potential.128,130
Side Effects
Amphetamines cause a number of side effects as a
result of their noradrenergic receptor activity130:
• α1: Increased blood pressure, headache, reflex
bradycardia, chest pain, dyspnea, nervousness
• α2: Dizziness, drowsiness, dry mouth, dyspnea,
bradycardia, syncopal episodes
• β1: Chest pain, cardiac arrhythmia, dyspnea
Side effects may be classified as acute or chronic.
Acute effects may include tachycardia, hypertension,
21
reduced appetite, insomnia, headaches, convulsions,
hallucinations, confusion, delirium, sweating, palpita-
tions, pupil dilation, rapid breathing, tremors, muscle
and joint pain, and paranoia.114,141 Initially, amphetamine
use results in an increased sex drive, but prolonged use
frequently reduces the libido and may cause erectile dys-
function.114,128 Amphetamine use can cause death from
cerebral hemorrhages, myocardial infarctions, and
arrhythmias.141 Amphetamines cause a redistribution of
blood away from the skin, thus limiting the normal cool-
ing of blood. The resultant heat stroke has claimed the
lives of multiple cyclists during grueling road races.114
Chronic amphetamine use by adolescents may result in
growth retardation.114 Chronic effects may also include
reversible hearing loss; tremors; nerve damage; vascular
disorders; liver, kidney, and lung damage; immune sys-
tem depression; restlessness; and altered sleep pat-
terns.128,141,142
Behavioral side effects include anxiety, depression,
mood swings, aggressive outbursts, panic attacks, and
paranoia.131,143–145 The euphoric effects and the indiffer-
ence, slowness in reasoning, and irresponsible behavior
associated with amphetamine use may affect judgment
needed in sports.114 Amphetamine withdrawal can cause
depression. Chronic high-dose amphetamine use can
cause persistent personality changes including ampheta-
mine psychosis. This disorder resembles paranoid schiz-
ophrenia but with a preponderance of paranoid and tac-
tile hallucinations.114 There is also mounting evidence
that heavy amphetamine abuse both initiates and main-
tains chronic schizophrenia.146
Testing and Regulation
In the United States and internationally, ampheta-
mines are Schedule II controlled substances.128,130 The
IOC and the NCAA have banned all amphetamines.
Major League Baseball does not explicitly ban ampheta-
mines, but testing for minor league contracts does
include these drugs among the banned substances.136
Amphetamines are readily detected in the urine.
Amphetamines are abused more as performance drugs
than as training drugs, so detection is most likely when
drug testing is performed during competition.136 The
screening test is performed by immunoassay. This is an
antibody-based testing method used for initial screening
of specimens. The immunoassay is sensitive to drug
groups, as opposed to individual specific drugs. False
positives can occur due to the presence of other related
drugs. Immunoassays can be performed in a laboratory
or on-site with an instant-type test. If the immunoassay is
positive, a gas chromatography/mass spectrometry
(GC/MS) test will be done. The GC/MS test is very spe-
cific. It is based on the physical and chemical properties
of the specific drug or metabolite to be measured. A pos-
itive result indicates the use of a drug containing
methamphetamine, amphetamine, or a drug that is
metabolized to these substances. A GC/MS confirmation
is considered to be the “gold standard” in the drug-test-
ing industry as it is said to be 100% accurate.147 Amphet-
amines can be detected from 2 to 4 days after use by
GC/MS technology.136 Table 13 contains the take-home
message for amphetamines.
Table 13. Take-home Message for Amphetamines
• Amphetamines may mask fatigue and increase anaero-
bic performance, possibly due to enhanced confidence
and increased aggression in healthy subjects.
• Serious physical and behavioral side effects including
death can result both acutely and chronically.
• Amphetamines are Schedule II controlled substances.
• Accurate screening and substance-specific tests are
available and are used.
ERYTHROPOIETIN
Mechanism of Action
The erythrocyte, or red blood cell, is the most com-
mon cell type in the blood. It is responsible for delivery
of oxygen to tissue beds. A mature red blood cell is
stuffed full of hemoglobin and contains almost none of
the normal cell organelles, with the nucleus, endoplas-
mic reticulum, mitochondria, and ribosomes extruded
from the cell during development.148 As a result, the red
blood cell cannot grow or divide; the lifespan of human
erythrocytes is limited to about 120 days. Worn-out red
blood cells are phagocytosed and digested by
macrophages in the liver and spleen to avoid cellular
debris that would attract the attention of inflammatory
cells.148 The only way to make more erythrocytes is by
stimulation of erythropoiesis in the hemopoietically
active bone marrow.149
Erythropoiesis involves differentiation from totipoten-
tial hematopoietic stem cells to pluripotential myeloid
stem cells. Cytokines stimulate the further maturation
into unipotential or committed precursor cells, including
burst-forming unit erythroid cells. Under the influence of
interleukin-3, granulocyte-macrophage colony-stimulat-
ing factor, and erythroid-promoting factor, burst-forming
unit erythroid cells mature into colony-forming unit ery-
throid cells. The colony-forming unit erythroid cells that
eventually give rise to the erythrocytes are the first cells
sensitive to erythropoietin (EPO).150
Erythropoietin is a glycoprotein hormone that consists
of 165 amino acids with a molecular mass of 18 kDa and
a 30 kDa carbohydrate component.150 In the fetus, it is
produced by hepatocytes; in the adult, 90% is produced
by peritubular cells in the kidneys and 10% by the liv-
er.150–152 Normal serum concentration is approximately
20mU or 10pmol. These concentrations vary throughout
the day and are greatest around midnight. Erythropoietin
half-life is 6 to 9 hours and it is inactivated in the liver.150
Erythropoiesis normally proceeds at a low basal level to
replace old red blood cells.149 Hypoxia, or lack of oxy-
gen, increases production of the hormone and can
increase red blood cell production as much as sixfold to
22
ninefold.149,150,153 Cobalt, thyroid hormone, adrenal corti-
costeroids, growth hormone, and stimulation of periph-
eral chemoreceptors all increase EPO production.150
Excessive tissue oxygen tension brings about a reduction
of produced EPO and consequently red blood cells.152
Erythropoietin stimulates proliferation of late burst-
forming unit erythroid cells and controls the maturation
rate of colony-forming unit erythroid cells by way of a
receptor-mediated effect.150 Specifically, binding of EPO
to an erythroid progenitor cell-surface receptor that
includes a p66 chain dimerizes this p66 protein.151,153 Ery-
thropoietin-receptor binding also engages a regulator of
inflammatory and immune genes, additionally inducing
survival proteins and cell proliferation.151,154 Other
hematopoietic growth factors can mature cells, have
overlapping capabilities to affect progenitor cells of sev-
eral blood cell lines, and also affect cells outside the
hematopoietic system, but EPO is specific for erythroid
progenitor cells and has little effect on other cells.152 This
specificity of EPO makes it a valuable pharmacological
tool.155 Additional effects of EPO include hematocrit-
independent and vasoconstriction-dependent hyperten-
sion, increased endothelin production, tissue renin up-
regulation, stimulation of angiogenesis, and proliferation
of endothelial and vascular smooth cells.151,154
Erythropoietin was originally prepared by concentra-
tion and purification of urine from patients exhibiting
high EPO levels, such as those suffering from aplastic
anemia and similar pathologies. This made EPO expen-
sive and thus hardly accessible for medical and
ergogenic purposes.152,156–158 Identification and characteri-
zation of the gene for EPO on chromosome 7 has
allowed for the larger scale production of recombinant
human EPO (rHu-EPO).150 In 2001, the FDA approved
darbepoietin-α, or novel erythropoiesis stimulating pro-
tein (NESP).150 Novel erythropoiesis stimulating protein
contains 3 additional N-linked carbohydrate chains and
has an approximately threefold longer serum half-life, 10
times the potency of EPO, and can, therefore, be admin-
istered less frequently to obtain the same response as
EPO.150,151,159,160
The normal therapy with rHu-EPO for the treatment of
anemia is 20 to 240 IU/kg 2 to 3 times per week by injec-
tion, in some populations, for the lifetime of the
patient.159 Dosages used by athletes to improve sports
performance have been higher than described above but
vary due to dose response. A recent study demonstrated
that regular low doses of rHu-EPO may produce readings
of hematocrit that fall within the allowable threshold for
regulated sports participation while still providing
enhanced aerobic performance.161 Erythropoietin and
NESP are administered by injection either subcutaneous-
ly or intravenously. Erythropoietin-stimulated erythro-
poiesis highly increases the demand for ferrous iron in
the production of hemoglobin and necessitates simulta-
neous iron injections.150
Effects on Performance
Sports events lasting more than 1 minute depend pre-
dominantly on aerobic energy production. Therefore,
performance will be limited by the ability to deliver oxy-
gen to the working muscles. Limiting factors in oxygen
uptake and delivery are cardiac output and oxygen-car-
rying capacity of the blood. The latter is determined by
hemoglobin content. Increased total body hemoglobin
levels may allow for increased endurance performance.
Several methods have been used to augment hemoglobin
content, some permitted (altitude training, hypobaric
oxygen tents) and others not permitted (blood doping,
blood substitutes, hemoglobin modifiers, plasma
expanders, actovegin, EPO and its derivatives). Based on
its mechanism of action, the authors would expect to see
positive effects of EPO use on aerobic performance.150
Use of rHu-EPO has been shown to positively affect
an athlete’s VO2max,162–165 increasing it by an additional
7% over altitude training, along with a 9% increase in
cycling time to exhaustion after 4 weeks of use. Earlier
studies provided support that rHu-EPO increased
VO2max and sport performance such as running.151 Pro-
longed low doses of rHu-EPO, rather than the original
higher dosages, were tested later for their effect on hema-
tocrit levels with submaximal and maximal exercise,
confirming the ability of the drug to maintain elevated
hematocrit levels 4 weeks after the final injection.166
Berglund and Ekblom167 administered 20 to 40 IU/kg
of rHu-EPO 3 times a week for 6 weeks to 15 healthy
men and found a significant pretest to posttest decrease
in heart rate during submaximal (200 W) bicycle
ergometer exercise.
Birkeland et al163 administered placebo or 181 to 232
IU/kg/wk of rHu-EPO for 4 weeks to male athletes. There
was a significant 7% pretest to posttest increase in
VO2max in the EPO group but no change in the placebo
group.
Connes et al164 administered rHu-EPO for 4 weeks to
16 endurance-trained athletes and found both an accel-
eration of the response of VO2 to submaximal exercise
and an increase in maximal exercise capacity at VO2max
during cycling exercise.
Wilkerson et al168 hypothesized that 4 weeks of rHu-
EPO treatment would produce a significant increase in
hemoglobin concentration and arterial blood oxygen-
carrying capacity, which would then increase VO2 during
ramp incremental exercise and speed VO2 kinetics during
a maximal-intensity step exercise. Although treatment
resulted in a 7% increase in both hemoglobin and VO2
peak, they found no significant effect on VO2 kinetics at
any level of exercise.
In summary, EPO appears to positively affect submax-
imal and maximal endurance performance. Not surpris-
ingly, EPO abuse has been documented among cross-
country skiers, cyclists, middle-distance runners, and
rowers.150
23
Medical Indications
Erythropoietin is administered medically to replenish
the body’s supply of this hormone and correct ane-
mia.159,169–171 Replacement of EPO alone, however, does
not suffice for full erythropoiesis to occur properly. For
example, this therapy is not fully effective in patients
with iron-processing deficiency or patients who have
problems with other aspects of erythropoiesis that are not
controlled by EPO.172
The FDA has also approved rHu-EPO for use in
patients with chronic renal failure, lympho-proliferative
diseases, myelodysplasia, myelofibrosis, and aplastic
anemia, and for patients after bone marrow transplanta-
tion.151,169 It is also indicated for use in patients scheduled
to undergo elective, noncardiac, nonvascular surgery.159
In addition, the drug has been used in premature infants
during the first 2 weeks of life, although this has been
controversial due to the questions remaining regarding
administration timing and dosing regimen.173 Current
research is studying use of rHu-EPO as a multifunctional
tissue-protective cytokine for vascular protection after
acute ischemic stroke.154,174
Side Effects
A phase-3 multicenter clinical trial of the use of rHu-
EPO in 333 patients on hemodialysis with uncomplicat-
ed anemia demonstrated the following side effects: myal-
gia, iron deficiency, hypertension, and seizures.175 Use of
rHu-EPO as a performance-enhancing drug has the
potential to increase blood viscosity and produce poten-
tially fatal thrombosis.176 In plain terms, rHu-EPO and
NESP have the potential to increase red blood cell
numbers, leading to thicker blood; when coupled with
dehydration during sports performance, this may result
in blood clots, thrombosis, and eventually heart
attacks.176,177 During 1987 to 1990, soon after rHu-EPO
became available, 18 young Belgian and Dutch high-lev-
el competitive cyclists died suddenly of heart attacks. No
definitive link between the deaths and rHu-EPO use was
established, but it was speculated that misuse of the drug
was responsible.177 Between 2003 and 2004, an addi-
tional 8 cyclists died of sudden heart attacks, with simi-
lar suspicions raised.178 The need for simultaneous injec-
tions with ferritin has the added possible adverse effect of
iron overload, with iron deposition in various tissues and
organs leading to organ failure including liver cirrhosis.
Increased ferritin levels (as detected in elite competitive
cyclists) also increase the risk of hepatic carcinoma.150
Testing and Regulation
Many competitive sports organizations including the
IOC, International Cycling Union, and International Ski-
ing Federation have banned the use of EPO and NESP.165
Unfortunately, there are problems with direct detection
in the blood or urine due to a short half-life (rHu-EPO)
and a structure similar to endogenous EPO. Also, perfor-
mance elevation outlasts detectable drug presence in the
body.179 Studies have focused on indirect markers of
increased erythropoiesis, such as serum levels of soluble
transferrin receptor, reticulocyte concentrations, and
hematocrit levels, to detect presence or previous use of
the drug. In 1997, the International Cycling Union enact-
ed a provision that prevented athletic participation for a
2-week period without formal suspension based on
blood hematocrit levels greater than 50% for men and
47% for women. A normal average hematocrit level for
cyclists is 43%.165
Serum levels of soluble transferrin receptor may be
used as an indirect marker up to 1 week after adminis-
tration of rHu-EPO. However, performance effects far
outlast this time period.163,165 Chemiluminescent immun-
odetection of EPO in urine after isoelectric focusing has
similar time limitations of use.180 One author181 noted that
for the most accurate detection in sports testing, the
physiological effects of EPO or NESP that last beyond
drug use should be measured and factored together with
the indirect blood markers. The IOC currently uses a
combination of blood and urine tests, but their validity
has been questioned successfully in a court of law.150
Table 14 contains the take-home message on EPO.
Table 14. Take-home Message for Erythropoietin
• Erythropoietin increases maximum oxygen consump-
tion. Effects far outlast use, as elevated hematocrit levels
are maintained up to 4 weeks after injection.
• Side effects from use to enhance sports performance
include increased blood viscosity and potentially fatal
thrombosis.
• The need for simultaneous ferritin injection increases
the chance of iron deposition disorder with multiorgan
failure.
• Testing involves a combination of blood and urine sam-
ples, but test validity has been questioned successfully.
ETHICAL AND LEGAL CONSIDERATIONS FOR THE
PHYSICAL THERAPIST
As discussed in the introduction to this monograph,
some ergogenic substances are controlled substances,
and the only legal way to obtain and use these sub-
stances is when prescribed by a medical physician. All
controlled and some uncontrolled ergogenic substances
are considered doping and banned by various sporting
organizations. This means that the physical therapist con-
fronted with a patient who reports using illicit or banned
substances has to deal with various legal and ethical
considerations.
With regard to these ethical considerations, members
of the American Physical Therapy Association (APTA) are
bound by oath by 2 documents that describe ethical pro-
fessional conduct: the APTA Code of Ethics182 and the
APTA Guide for Professional Conduct.183 Some state leg-
islatures have adopted these documents as part of the
physical therapy state practice act, adding a legal dimen-
sion to ethical conduct as described in these docu-
24
ments.184 Other ethical considerations are less specific to
the profession but concern society as a whole.
Currently, society and sporting organizations con-
demn on ethical grounds the use of banned ergogenic
substances as providing an unfair advantage in competi-
tion. However, a prominent commitment for all health
care providers is the prevention of adverse health out-
comes. Perhaps for a health care provider, the question
of whether a substance is in fact truly ergogenic and
whether an athlete is using said substance should be less
relevant than the question of whether the use of said sub-
stance could adversely affect the athlete’s health.185 Mon-
itoring the athlete’s health by setting standards for physi-
ological parameters with or without the use of ergogenic
aids would not only level the playing field but also pro-
vide strict control against athlete morbidity and even
mortality. For example, permitting the use of relatively
cheap EPO, but at the same time setting safe upper lim-
its for hematocrit for sports participation, might allow
athletes that cannot afford legal methods of elevating red
blood cell count (eg, altitude training and hypobaric oxy-
gen tents) to safely compete with those athletes that do
have the required financial backing.185 Revising doping
regulations based on this paradigm would allow society
to concentrate limited resources on the truly dangerous
methods and substances. This position would seem most
consistent with principle 4.1 (A) of the APTA Guide for
Professional Conduct,183 which requires the therapist to
act in the client’s best interests, but obviously this issue
requires discussion at the societal level.
One ethical question specific to the profession relates
to the role of the physical therapist in providing a patient
with education and advice regarding the use of
ergogenic substances. These substances are no different
from other pharmacological or nutritional substances
used by the patient in that the physical therapist needs to
be aware of intended and adverse effects on the patient
and the possible interaction of these substances with the
physical therapy interventions provided. Ahrendt10 sug-
gested that the physician confronted with this situation
should make sure to be knowledgeable about the topic
and then provide the patient with detailed information
about what is known and not known with regard to a
specific product based on current research with an in-
depth discussion of the potential adverse effects. The
information in this monograph should allow a physical
therapist to do just that. Providing patient education is
consistent with principle 8.1 (A) of the APTA Guide for
Professional Conduct,183 which indicates that the thera-
pist has the responsibility to provide the patient with
accurate and relevant information related to the patient’s
condition and plan of care. However, providing a patient
with a specific plan of care that includes nutritional and
pharmaceutical interventions is not part of the physical
therapy scope of practice. In principle 11.1, the Guide
for Professional Conduct183 discusses the need for con-
sultation and referral to health care professionals with
specialized knowledge and skills (ie, in this scenario, a
physician or nutritionist).
Another ethical problem arises from the fact that
many of the substances discussed in this monograph are
illegal to use if they are not on prescription by a physi-
cian for medical purposes. What is the ethical responsi-
bility of the therapist who has knowledge of the fact that
the patient is engaging in illegal behavior by having pro-
cured and used controlled substances without a physi-
cian’s prescription? Principles 1.1 (A) and 2.3 (A)
describing the need to respect the patient’s choices and
the need for confidentiality would seem to apply.183 How-
ever, when it becomes clear to the therapist that the
patient is not only using but also trafficking these sub-
stances and selling them to other users or if the therapist
becomes aware of the mode of supply for the patient, the
therapist’s ethical responsibilities with regard to the
health status in the community at large, described in
principle 10.2 (B),183 would seem to supersede the prin-
ciples related to the individual mentioned earlier, and
the law enforcement community should be contacted.
The APTA Ethics and Judicial Committee is meant to pro-
vide more clarity on these 2 issues in a March 2006
meeting.
There are many additional ethical questions related to
patients abusing certain illegal ergogenic substances that
have the ability to cloud patient judgement.186 An
impaired response to our therapy intervention potential-
ly puts the patient at risk for injury. But how do we
determine if the patient is under the influence of a sub-
stance that may affect judgment? If the patient does not
voluntarily report relevant substance abuse, then the
therapist has no way to detect, for example, the use of
alcohol, amphetamines, other stimulants, or AAS, which
may all potentially impair response to treatment. Do we
proceed with treatment or do we deny treatment? Do we
have the patient sign a release of liability form and pro-
ceed with treatment, putting the patient at risk for iatro-
genic injury? Do we report the reason we denied treat-
ment and put the patient at risk of losing insurance cov-
erage? And if we do decide that patient judgment is
impaired, can we allow patients to leave the clinic in
their vehicle, endangering both themselves and others on
the road? For any specific ethical questions, the APTA
suggests that you refer to your state board (personal com-
munication, APTA executive office, February 2006).
There are, of course, also legal considerations. As not-
ed by Bennett,184 a therapist may have an ethical duty to
perform a certain action, but if no law mandates such
action, the therapist has no legal obligation. Conversely,
if a therapist has an obligation under law to perform a
certain action, then that law is binding even if there is no
corresponding documented ethical obligation. Federal
legislation dealing with controlled substances187 contains
provisions for requiring testimony from witnesses (Sec-
tion 884) and for fining and imprisoning people who fail
to notify authorities of their knowledge of drug trafficking
25
activities (Section 961). This would certainly seem to
impact therapist decisions based solely on ethical guide-
lines regarding patient confidentiality. Legal enforcement
of ethical guidelines incorporated in state practice acts
suffers from unclear definitions184 but adds another level
of complexity to decision making. The authors of this
monograph suggest that therapists with questions on
these issues seek legal counsel.
The topic of ergogenic substance use by patients in
physical therapy raises many unanswered ethical and
legal concerns. The authors of this monograph do not
have all of the answers; seeking the assistance of the state
physical therapy licensing board or legal counsel may be
required. Further discussion within society as a whole
and within our professional organization in particular is
clearly needed in order to provide additional guidelines
for clinicians.
CASE STUDIES
Case Study 1
Subjective information
Annika is a 24-year-old right-hand dominant
Olympic-level competitive rower. Her current level of
training is very high in anticipation of an Olympic qual-
ifying meet and includes both an increased volume and
intensity of work on the water, on the rowing ergometer,
and in the weight room. Over the last 3 weeks she has
noted a general fatigue and discomfort in the right arm
during but even more so after a workout. Overhead
activities also bring on these symptoms. She has also not-
ed some intermittent purple discoloration of the right
hand and paresthesia in the ulnar forearm and hand,
especially upon awakening and with exertion. Her pre-
vious and concurrent medical history is unremarkable as
is her family history except for an inherited coagulopathy
involving factor V Leiden. Annika reports using oral con-
traceptives but no other medications. As she is a direct
access patient, she has had no further diagnostic tests
done and, in fact, has not seen a physician for this cur-
rent complaint. Annika reports being in overall good
general health.
Objective findings
• Observation: The patient has a mesomorphic build
with a moderate forward head posture and right-
sided elevated shoulder girdle. The right arm is
notably cyanotic.
• The superficial veins of the arm are dilated and there
is general nonpitting edema of the right arm.
• Palpation reveals tenderness along the right axillary
vein in the medial bicipital sulcus.
• Active range of motion: Cervical and upper extremi-
ty range of motion are bilateral within normal limits
except for shoulder flexion and abduction right,
which are pain free but limited by 15° as compared
to the right.
• Elevated arm stress (Roos) test produces right arm
discomfort, discoloration, venous distension, and
ulnar distribution paresthesia within 30 seconds.
These findings are all symptomatic of subclavian and
axillary vein deep venous thrombosis.188 On further ques-
tioning and after discussion of patient confidentiality
requirements in physical therapy, Annika hesitantly
reports using rHu-EPO in an attempt to increase her ath-
letic performance. She is referred to the emergency
department of the local hospital with the clinical suspi-
cion of upper extremity deep venous thrombosis. A right
subclavian vein thrombus is subsequently diagnosed by
contrast venography, and treatment with anticoagulants
is immediately initiated.
Guide to Physical Therapist Practice diagnosis
The diagnosis according to the Guide to Physical
Therapist Practice189 is:
• Practice pattern 6A: Primary prevention/risk reduc-
tion cardiovascular/pulmonary disorders.
• Practice pattern 4D: Impaired joint mobility, motor
function, muscle performance, and range of motion
associated with connective tissue dysfunction.
• Practice pattern 5F: Impaired peripheral nerve
integrity and muscle performance associated with
peripheral nerve injury.
Discussion
One of the major adverse effects of EPO is the
increased risk for thrombosis. Oral contraceptive use
(especially of so-called third-generation contraceptives
containing desogestrel or gestodene) has been associat-
ed with an increased relative risk for venous throm-
boembolism.190 The relative risk for upper extremity deep
venous thrombosis is increased in women with factor V
Leiden coagulopathy when combined with oral contra-
ceptive use.191 Repetitive mechanical insult to the subcla-
vian vein in the thoracic outlet in combination with the
inherited coagulopathy and medication-induced hyper-
coagulability increases the likelihood of upper extremity
deep venous thrombosis as the reason for the current
complaints.
Case Study 2
Subjective information
John is a 32-year-old amateur competitive body-
builder. His workout routine consists of 5 days per week
of high-intensity resistance training. He does not care
much for aerobic exercise and limits aerobic activities to
a 10-minute to 15-minute warm-up before his workout.
For 5 weeks now, he has noted progressive left lateral
elbow pain. The pain started after he was trying some
pliometric push-ups in an attempt to increase his bench
press performance. During one of the impacts with the
arms outstretched during this exercise he felt something
“shift” in his elbow. The pain now limits him with activi-
ties involving gripping, forearm rotation, and elbow flex-
ion, especially with the forearm pronated. He notes no
sensory abnormalities but has loss of strength due to
26
pain. His previous medical history includes multiple
tendinopathies in the shoulders, knees, and ankles. A
family history is positive for myocardial infarction and
cerebrovascular accidents. John denies any medication
use. A systems review yields no remarkable findings.
John reports being in good health but has lately been a
bit fatigued, which he blames on a high training volume.
Objective findings
• Observation: The patient has a very muscular meso-
morphic build with rounded shoulders and a for-
ward head posture. Generalized acne and multiple
striae are noted, as is a seemingly increased carrying
angle for the left elbow.
• Active range of motion: Range is similar bilaterally
for the wrist and elbow with the exception of
decreased forearm supination and decreased wrist
radial deviation left versus right.
• Manual muscle tests of the wrist and elbow are 5/5
bilaterally with pain noted on wrist extension, fore-
arm supination, and elbow flexion with pronation
left.
• Neurodynamic tests for a radial nerve distribution
are negative bilaterally.
• Varus stress test on the left causes lateral elbow pain,
and excursion is decreased compared to the right
elbow.
• Passive accessory motion tests in the wrist and elbow
are normal bilaterally with the exception of
decreased lateral glide of the left forearm.
• Palpation reveals tenderness over the extensor carpi
radialis brevis tendon on the left but with no local
swelling or increased temperature.
Physical therapy diagnosis
The physical therapy diagnosis is: tendinopathy of the
left extensor carpi radialis brevis and abducted ulna syn-
drome on the left.
Physical therapy intervention
John was educated as to the physical therapy diagno-
sis, prognosis, and proposed treatment plan. Treatment
was initiated with a varus-type (Stoddard) grade V manip-
ulation to the left elbow and deep transverse friction
massage to affect changes associated with degenerative
tendinopathy in the extensor carpi radialis brevis tendon.
This was followed with grade IV-IV+ lateral glides of the
left forearm at the elbow to affect the hypothesized
humero-ulnar positional fault. Ice was applied after
manipulation to decrease any possible excessive inflam-
matory response. John was educated regarding a modi-
fied workout technique, extensor carpi radialis brevis
stretches, and careful eccentric strengthening of the wrist
extensor muscles.
Reevaluation
John was treated with the above program 3 times over
3 weeks and noted a decrease in the elbow pain. During
a conversation with the therapist about ergogenic nutri-
tional supplements, John mentions his prolonged use of
different regimens of oral and injectable AAS since tak-
ing up bodybuilding some 10 years ago. When the ther-
apist decides to introduce John to a more varied workout
regimen by introducing an upper body ergometer exer-
cise in the treatment plan at the third visit, John has to
stop this new exercise after 5 minutes because of chest
and left supraclavicular pain. The pain subsides rapidly
after stopping the exercise. John reports that over the last
few months, similar pains have made him cut back on
his aerobic exercise. Further questioning reveals that
John has failed to mention progressive fatigue, shortness
of breath, and palpitations during the previous systems
review. The therapist refers John to his physician with a
request for evaluation of the cardiovascular system. An
exercise stress test and coronary arteriography show
coronary artery disease. Blood tests showed greatly
increased levels of triglycerides and low-density lipopro-
tein cholesterol. John is subsequently treated with a
coronary stent implant and medically managed with diet
and cholesterol-lowering medication.
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NOTES

34
 Orthopaedic Section Independent Study Course 16.1.5
Ergogenic Substances
REVIEW QUESTIONS

1. In the United States, over-the-counter nutritional 6. Which of the following statements regarding alco-
supplements: hol use is true?
a. are regulated by the Dietary Supplement Health a. alcohol is useful to warm up when exercising in
and Education Act. cold weather.
b. are strictly controlled with regard to marketing b. all alcohol in the body is from external sources.
claims and content labeling. c. exercise burns alcohol, leading to sobriety.
c. fall under the jurisdiction of the Food and Drug d. percentage of body fat affects tolerance to
Administration. alcohol.
d. have been tested and regulated for safety and
efficacy. 7. Fetal alcohol syndrome may include:
a. facial abnormalities.
2. Which of the following effects is reversible in b. growth deficiency.
women using anabolic-androgenic steroids? c. microcephaly.
a. deeper voice. d. all of the above.
b. increased facial hair.
c. male-pattern baldness. 8. Which of the following speeds up the elimination of
d. oligomenorrhea. caffeine?
a. alcohol use.
3. Use of androstenedione leads to the most significant b. cigarette smoking.
dose-dependent increases in the serum concentra- c. high-intensity exercise.
tions of: d. oral contraceptive use.
a. estradiol.
b. follicle-stimulating hormone. 9. Caffeine withdrawal can result in:
c. luteinizing hormone. a. headache.
d. testosterone. b. irritability.
c. muscular twitching.
4. Which ergogenic substance has no deleterious d. all of the above.
effects on blood lipid profiles:
a. androstenedione. 10. Amphetamines have been abused by athletes to:
b. beta-hydroxy-beta-methylbutyrate. a. increase hematocrit levels.
c. growth hormone. b. increase muscle mass.
d. injected anabolic-androgenic steroids. c. decrease muscle damage.
d. maintain a low body weight.
5. The cellular role of creatine is:
a. a cellular buffer to excessive adenosine diphos-
phate concentrations.
b. increasing transmembrane osmotic gradient.
c. resynthesis of muscle adenosine triphosphate.
d. all of the above.

35
 1. a
2. d
3. a
4. b
5. d
6. d
7. d
8. b
9. d
10. d
ANSWERS