Sports Pharmacology: Drug Use and Abuse

Testosterone is the primary male hormone in the body. It
has both anabolic and androgenic effects. Testosterone is formed in the
body from cholesterol through a series of reactions. There are several
pathways that lead to the formation of testosterone from cholesterol.
One way is from dehydroepiandrosterone (DHEA) being converted into
androstenedione and then testosterone. Another way is DHEA to
5-androstenediol and then testosterone. Yet another is DHEA to
androstenedione, to 4-androstenediol, and then testosterone. Knowledge
of the cholesterol to testosterone pathway is important because most
synthetic anabolic steroids and prohormone supplements are based on
tinkering with the various compounds in this pathway. The principal
active metabolite of testosterone is 5 α-dihydrotestosterone
(DHT). DHT has a much higher affinity to androgen receptors than
testosterone. Also, it is important to note that androstenedione can be
converted to estrone instead of testosterone and continue on to form
estradiol. Not only can androstenedione end up forming estradiol, but
testosterone itself can be changed to estradiol.

The ergogenic effects of testosterone have been used for
the greater part of the 20th century. At the 1936 Olympic Games,
athletes used testosterone. There have been numerous studies that have
proven that exogenous testosterone supplementation can increase lean
body mass (LBM), decrease body fat, and increase strength and power.
Testosterone has been shown to allow an athlete to perform greater
volumes of work in each training session, to perform more sessions each
day, and to recover more quickly from each session. Testosterone can be
taken as a pill (75 to 100 mg qd), as an injection (200 to 250 mg qd),
as a transdermal patch, or as a skin cream.

Exogenous testosterone use is associated with a host of
dangers for an athlete. The androgenic effects include premature
baldness, facial acne, body acne, and an increase in cardiovascular
disease. In men, there is also a decrease in sperm production, a
decrease in testicle size, and an increase risk of prostate cancer. The
testosterone metabolite DHT, because of its high androgen receptor
affinity, significantly contributes to these effects. Besides the
serious health risks to an athlete taking testosterone, there are also
the legal risks. The National Collegiate Athletic Association (NCAA),
IOC, U.S. Olympic Committee (USOC), and various other governing sports
bodies have banned testosterone use, which is tested by measuring the
ratio of testosterone to epitestosterone (T:E ratio) in an athlete’s
urine. A normal

T:E ratio is 1:1, but the illegal supplementation cutoff value is 6:1.

Steroids are believed to have a variety of effects on
the human body. They are thought to have an anticatabolic effect.
Steroids compete with glucocorticoids for glucocorticoid binding sites,
leading to a decrease in the concentration of cortisol in the body.
Cortisol is one of the major stress hormones that rise as exercise
intensity increases and leads to increased muscle breakdown. Steroids
prevent muscle breakdown associated with exercise. Besides
anticatabolic effects, steroids are more often associated with their
anabolic effects. Steroids cause nitrogen retention by forming an
androgen-receptor complex. This complex is transported to a nucleus of
a muscle cell, where it binds to complementary regions on DNA. This
leads to activating transport RNA and increased protein synthesis,
which leads to increased muscle growth.

Steroids have effects on other tissues in the body,
including stimulating erythropoiesis and causing increased bone marrow
activity, increasing hemoglobin, and increasing reticulocyte count.
They also create larger, stronger bones by stimulating osteoblast
production, thus increasing levels of 1,25-dihyroxy vitamin D, and
producing bone matrix proteins.

Testosterone in the body can be converted to a highly
androgenic metabolite (DHT) or to estradiol (an estrogen). Neither of
these conversions is beneficial. Increased estradiol levels lead to
feminization of male sex traits, such as gynecomastia and a
higher-pitched voice. The term aromatization
describes the conversion of steroids into estradiol. New generations of
steroid manufacturers are always trying to find ways to prevent
aromatization. Testosterone is converted into DHT by the enzyme 5α-reductase
with the aid of androgen receptors. DHT causes male pattern baldness,
an increased risk in prostate cancer, and many other androgenic side
effects. Because testosterone, the original steroid, has both anabolic
and androgenic effects, all synthetic steroids have both effects as
well, but to varying degrees. New generations of steroids have
attempted to have a decreased affinity for androgen receptors in favor
of increased anabolic activity. Another important term is C-17 alkylation. This refers to the concept that the number 17 carbon in a steroid is capable of becoming a 17α derivative or a 17β
ester of testosterone. This difference is important because
esterification makes the steroid more fat soluble, delays absorption in
the blood, and can be metabolized in the liver. Injectable steroids are
17β esters or non-17α-alkylated steroids. Oral steroids are 17 α-alkylated
steroids and resist metabolism in the liver. This means a smaller dose
of steroids are required orally to produce an equal effect, but it also
means that 17 α-alkylated steroids are much more hepatotoxic. The term cycling
applies to athletes using steroids for a period of several weeks,
usually 6 to 12, and then stopping usage for another period of time. Stacking refers to athletes using several different steroid agents all at the same time. Pyramiding means gradually increasing the dose of steroids over a period of time.

When castrated animals were given steroids, the result
was an increase in nitrogen retention and increased lean muscle mass.
In rats given steroids, the effects were an improvement in recovery
after exercise, an increase in force generating, and improved recovery
time from muscle contusions. Steroids have a variety of medicinal uses:
to treat hypogonadism, to provide palliative care in breast cancer, to
treat angioneurotic edema, and to treat acquired immune deficiency
syndrome (AIDS)-related cachexia. Studies have shown that oxandrolone
leads to hypertrophy of the diaphragm. This causes increased expiratory
and inspiratory muscle strength, as well as an increase in pulmonary
vital capacity. An increase in lean body mass occurs after taking
steroids. One study on the effect of steroids showed that males taking
steroids gained an average of 19.9 kg body weight and increased their
maximum bench press by 47%. Muscle biopsies of athletes taking steroids
showed an increase in both the average muscle fiber size and the number
of muscle fibers. Although there is overwhelming evidence to show that
steroids increase muscle mass, decrease body fat, increase strength,
and decrease recovery time, there are not significant data to show that
steroids improve aerobic performance.

Steroids have significant documented health risks on a
variety of organ systems. They have proven CNS effects, including
increased aggression, mood swings, and increased sexual arousal.
Steroid users are significantly more likely to have a major mood
disorders (mania, hypomania, or major depression) than nonusers.
Steroids also have profound effects on skin, such as oily hair, oily
skin, alopecia, increased sebaceous cysts, striae distensae, and facial
and back acne. They cause premature closure of bone growth center,
which leads to stunted growth in young steroid users. Another
musculoskeletal effect of steroid use is an increased incidence of
tendon ruptures as a result of excessive loads placed on tendinous
insertion points. The effects of steroids on one’s liver are also quite
profound. Liver function tests (LFTs) find increased levels of
aspartate aminotransferase, alanine aminotransferase, lactate
dehydrogenase, alkaline phosphatase; and peliosis hepatis, which is the
development of blood-filled cysts in the liver. If these cysts rupture,
it is a life-threatening matter. Steroid use increases the risk of

developing liver cancer. Exogenous steroids create numerous reproductive and endocrine changes in a user’s body.

In males, steroids cause feedback inhibition along the
hypothalamic-pituitary-gonadal axis. High levels of steroids cause the
body to decrease production of luteinizing hormone and
follicle-stimulating hormone, thus causing secondary hypogonadotrophic
hypogonadism. This results in a decrease in mean testicular length, a
decrease in sperm count, a decrease in sperm mobility, a decrease in
sperm density, and an increase in infertility but no change in libido.
The aromatization of steroids in males also causes gynecomastia and an
increased risk of prostate cancer. In women, steroids cause hirsutism,
voice deepening, clitoral hypertrophy, a decrease in breast size,
amenorrhea, and male pattern baldness. In males, discontinuing steroids
leads to a reversal of all the testicular and spermatogenic changes,
but the changes in a female steroid user’s body are irreversible. The
cardiovascular system is also affected by exogenous steroid use. An
increase in total cholesterol levels, an increase in low-density
lipoprotein (LDL) levels, a decrease in high-density lipoprotein (HDL)
levels, and a decrease in triglyceride levels are all well documented
in steroid users. Steroid users experience cardiac hypertrophy and
hypertension and are at increased risk for stroke or myocardial
infarction. Injection of steroids also leads to an increased risk of
exposure to human immunodeficiency virus (HIV), hepatitis B, and
hepatitis C.

Although steroids have medical benefits that extend
beyond the athletic field, the dosages of steroids used are much lower
than those used by athletes for performance enhancement. For example,
the recommended dose of Dianabol is 2.5 to 5.0 mg/day; however, one
study showed that athletes using Dianabol were consuming 6,000 mg in a
2-week period, well above the recommended dose. It is important to
emphasize to athletes that many of the dangerous effects of steroids
can be reversed by discontinuing usage. LFT results, show that
cholesterol levels, and cardiac hypertrophy return to normal,
hypertension disappears, and the risks of stroke and myocardial
infarction are decreased. However, it is not known whether the
long-term risks of developing prostate and liver cancer remain
increased.

Between 4% and 12% of high school males have used
steroids. Use in NCAA athletes is 14% to 20%, and the number is higher
for professional athletes. Steroid users have also been shown to be
twice as likely to use tobacco, three times more likely to use
marijuana, four times more likely to use cocaine, and ten times more
likely to use amphetamines. They may consume three times as many
alcoholic drinks in a week than nonusers. This self-reported study
showed that, of the athletes who used steroids, 70% had gotten into a
fight, 45% had gotten injured, 44% had performed sexual misconduct, and
41% had run into trouble with the law. These results have raised the
question of whether steroids should be considered a gateway drug. For a
summary of the adverse effects of steroids, see Box 3-1.

When people today hear the word “andro,” the image that
comes to mind is Major League Baseball’s record home run season of 1998
and the ensuing supplement scandal. Androstenedione is a steroid
precursor to testosterone. It is synthesized in the testes but can be
made from DHEA peripherally. Variants of androstenedione that can be
found as prohormones in supplements include 5-androstendione,
4-androstenediol, 5-androstenediol, 19-norandrost-4-enedione,
19-norandrost-5-enediol, and 19-norandrost-4-enediol. All are alleged
to increase serum levels of testosterone. By increasing serum
testosterone, exogenous androstenedione supplementation has been touted
to increase strength, decrease body fat mass, and increase muscle mass.

No study has yet shown that androstenedione increases
strength or improves athletic performance, but decreases in
testosterone have resulted from androstenedione use. It has been
hypothesized that there is a down-regulation of endogenous testosterone
production in the face of exogenous androstenedione supplementation.

Androstenedione in males increases serum levels of the
feminizing hormones estrone and estradiol. This can lead to
gynecomastia. A decrease in serum levels of HDL has also been shown,
which can increase the risk of coronary artery disease. No data exist
on the long-term adverse effects of supplementation with
androstenedione.

DHEA supplemented in rats leads to decreased body fat,
decreased cholesterol levels, and increased insulin sensitivity. One
important physiologic difference between rats and humans is that DHEA
is not produced in rat adrenal glands. It was believed that DHEA would
lead to increased levels of growth hormone and insulin-like growth
factor 1 (IGF-1), which would lead to increased muscle mass. Also, DHEA
was thought to have an anticatabolic, accelerating recovery by
counteracting the effects of glucocorticoids. Exercise has been shown
to cause a rise in DHEA levels, with the half-life of DHEA at 25
minutes and conjugated sulfate DHEA at 10 hours.

Doses of up to 1,100 mg/day of DHEA lower HDL levels,
cause irreversible gynecomastia in men, increase estrone and estradiol
levels, and increase risk of coronary artery disease. There have been
case reports, but no studies, showing that DHEA causes voice deepening,
virilization, hair loss, and hirsutism in women, as well as causes
irreversible gynecomastia in men. The long-term effects of DHEA are
unknown, but it is believed they include increased risks of breast,
uterine, and prostate cancer.

Human growth hormone (hGH), also called somatotropin,
has a host of roles in the body. It stimulates protein synthesis,
increases tissue growth by increasing nitrogen retention, and inhibits
glucose utilization by promoting lipolysis. Other functions include
increasing cardiac output, increasing sweat rate, increased wound
healing, increased bone formation and bone mass, increased LBM,
decreased fat mass, and improved thermal homeostasis.

With endogenous hGH responsible for many beneficial
functions in the human body, it was theorized that exogenous hGH could
enhance athletic performance. In individuals who are growth
hormone-deficient, supplementation with hGH led to increased muscle
mass, increased muscle strength, increased LBM, and decreased fat mass.
This anabolic effect of exogenous hGH supplementation on growth
hormone-deficient patients lasted for 5 years after discontinuing
supplementation. Muscle fiber-type ratios were also altered, as
exogenous hGH increased the percentage of type II fast-twitch fibers
and decreased type I slow-twitch fibers. Another medical use for
exogenous hGH is in malnourished, elderly patients. Somatotropin
decreases with age, as body fat percentage rises and LBM decreases.
Supplementing hGH can lead to decreased body fat and increased LBM.
Supplementation with hGH for only a few weeks can markedly increase
bone and collagen turnover for several months.

An athlete using hGH may experience no increase in

strength and no effect on athletic performance even while gaining an
increase in whole-body protein synthesis and LBM and having decreased
in body fat.

Exogenous hGH supplementation poses significant health
risks. Elderly patients supplemented with hGH had an increased
incidence of myalgias, arthralgias, and edema. The edema is caused by
increased sodium and water retention. Supplementation increases left
ventricular hypertrophy, hypertension, increased insulin resistance,
and increased lipoprotein A, which is associated with increased
cardiovascular risks. Increased IGF-1s is linked to lung and colorectal
cancer. Excessive exogenous hGH also leads to acromegaly. During the
1990s, hGH was often extracted from cadaver pituitary glands; this led
to the development of Creutzfeldt-Jakob disease, a bovine spongiform
encephalopathy, in seven patients.

Salbutamol, terbutaline, and Clenbuterol are all β₂-adrenergic
receptor agonists. Salbutamol is a short-acting drug used in the
treatment of respiratory disease as a bronchodilator. Terbutaline is a
tocolytic agent used in pregnancy to stop uterine contractions during
preterm labor. Clenbuterol is another bronchodilator used in the
treatment of asthma. Clenbuterol can be inhaled, injected, or taken
orally. Salbutamol is used in the cattle industry as an anabolic agent,
as it increases cattle size. Of the β₂-agonists,
Clenbuterol is the most widely used in athletic competition. It is
considered a stimulant and a weight-loss aid. This is because of brown
adipose thermogenesis. Brown adipose tissue is fat tissue in the body
that contains large arterioles with a high number of red blood cells.
Brown adipose cells have mitochondria that create energy. Because there
are β₂-adrenore-ceptors in
brown adipose tissue, Clenbuterol can stimulate activation of these
receptors, which causes brown adipose thermogenesis.

Large doses of Clenbuterol cause an increase in LBM and a decrease in fat mass in animals. Oral or injected Clenbuterol of 20 µg
twice a day showed an increase in quadriceps force in orthopaedic
patients. Administration of salbutamol to cyclists improved pulmonary
function but did not have any effect on performance. There are no
studies that show β₂-agonists have any effect on strength and performance.

Clenbuterol caused subjects to have tachycardia,
increased headaches, muscle tremors, heart palpitations, and muscle
cramps. In rats, Clenbuterol caused cardiac hypertrophy. There have
been reports of withdrawal symptoms when athletes stop taking
Clenbuterol.

Creatine is involved in adenosine triphosphate (ATP)
synthesis. In cells, creatine phosphate combines with adenosine
diphosphate and is converted into ATP and creatine by the enzyme
creatine kinase. Ingested creatine levels peak in the body from 60 to
90 minutes after oral intake. By increasing the levels of creatine,
this leads to greater resynthesis of creatine phosphate by 12% to 18%.
Creatine phosphate is the body’s primary immediate source of ATP.
During intense anaerobic exercise, ATP is consumed in the first 10
seconds. The more ATP that is available, the more strength and power a
muscle can produce, and the longer an athlete can maintain higher
maximum power output. Creatine also serves to buffer the muscle pH by
using a hydrogen ion to resynthesize ATP. This delays muscle fatigue
and shifts an individual’s lactate threshold. Creatine also increases
whole-body nitrogen retention, increases water retention at the
cellular level, and increases myofibrillar protein synthesis.

Creatine is one of the most recently studied
supplements, with nearly 100 scientific studies having been done, the
vast majority of which within the past 10 years. Most creatine

studies
use a dose that consists of a loading period of anywhere from 4 to 7
days of 20 g/day, followed by a maintenance dose of 5 g/day for the
rest of the study length. Chronic resistance training has been shown to
produce gains in LBM of up to 1 kg/month. One-week supplementation with
creatine can produce 1 to 2 kg of LBM. Creatine use has been associated
with a larger LBM gain and significantly greater increase in strength
than carbohydrate supplementation or use of a combination of
carbohydrates and protein. Combining creatine supplementation was shown
to lead to a greater increase in lean muscle mass when compared with
placebo and creatine alone. Combining creatine with protein
supplementation led to a 10% increase in muscle mass and strength gains
when compared with protein alone. The strength and LBM effects lasted
even 4 weeks after creatine use was discontinued. Creatine
supplementation increases lean muscle mass by 0.36% per week over
placebo or about a 2.2 kg increase in LBM over a 6- to 8-week period.

It has been well documented in the literature that
creatine increases maximal strength. Although the evidence supports the
fact that creatine supplementation does improve strength, some studies
have not found this to be the case. One study of college football
players found no difference in 1RM squat, anaerobic muscle endurance,
body fat loss, or LBM between placebo and two different methods of
creatine dosing.

Creatine also has an ergogenic effect on high-intensity,
repeated sprints. In looking at 61 studies of creatine supplementation
on running, swimming, or rowing sprints lasting less than 30 seconds,
45 studies found statistically significant evidence of creatine
improving athletic performance. Creatine supplementation seems to aid
in recovery of creatine phosphate stores in recovery periods less than
6 minutes but has no added benefit in periods of 6 or more minutes.
Single bouts of high-intensity cycling and swimming have shown no
benefit from less than 1 week of creatine supplementation, but
high-intensity repeated efforts have shown improved performance with
creatine versus placebo. In short sprints from 6 to 30 seconds in
length, there is an average improvement of 1% over placebo with
creatine supplementation. In a sprint that may last only 25 seconds, a
decrease in time of 1% equals 0.25 seconds—at the world-class level,
this is a huge difference since medals can be won or lost in 0.01
seconds.

Creatine’s effect on longer anaerobic and aerobic
endurance events is debated, with some studies showing improvement and
others showing no improvement. For longerdistance endurance events, the
extra LBM from muscle and water retention may slow runners and swimmers
down.

The major reported side effect of creatine versus
placebo has been an upset gastrointestinal system. Other studies have
shown no difference between the side effects in the creatine and
placebo groups. There have been case reports of increased muscle
cramping, believed to be the result of creatine’s ability to bring
water into the cell. Because creatinine is a major breakdown product of
creatine, there has been concern about how creatine ingestion may
affect renal function. It has been shown that increased consumption of
creatine does lead to an increase in serum creatinine levels.

One
study examining creatine supplementation over a 4-year period found no
adverse reactions, no change in cholesterol levels, no change in LFTs,
no change in hGH levels, no change in cortisol levels, and no change in
testosterone levels. Another study of NCAA football players having
taken creatine for 3 years showed no effect on kidney or liver
function. Players had normal LFTs, normal creatinine, normal blood urea
nitrogen, normal creatinine clearance, and normal urea levels after
consuming creatine for 3 years. There were no reported side effects.
Other retrospective studies have also found no significant adverse
effects up to 5 years after ingesting creatine. However, there have
been no studies of the effect of creatine longer than 5 years.

Meta-analysis of supplementation with HMB compared nine
studies that showed a statistically significant increase in LBM of
0.28% body mass per week and 1.40% single repetition maximal strength
gain per week versus placebo groups.

As for the recuperative abilities of HMB, there is
evidence that it decreases muscle breakdown, as evidenced by decreased
protein breakdown and increased muscle recovery and lower levels of
lactate dehydrogenase and creatine phosphokinase postexercise.

HMB supplementation has not been associated with changes
in serum testosterone, cholesterol, triglyceride, urea, or glucose
levels, renal function, LFTs, and lipid levels. There have been no
reported side effects in any of the studies examining use of HMB.

The structure of caffeine is similar to adenosine. In
the body, caffeine binds to adenosine cell membrane receptors found in
the brain, heart, smooth muscle, adipocytes, and skeletal muscle.
Caffeine can simultaneously affect a wide number of tissues in the
body. It stimulates the CNS and increases the release of epinephrine.
Caffeine has been shown to increase heart rate, increase metabolic
rate, increase respiratory center output, decrease perception of pain,
decrease fatigue, and increase fat oxidation. A main benefit of
caffeine’s effect on performance has been linked to increased fat
oxidation, causing increased serum free fatty acid levels and thereby
sparing muscle glycogen. However, there is another new mechanism that
shows how caffeine effects substrate utilization during exercise.
Caffeine has been shown to decrease plasma potassium (K⁺) levels. This is significant because during exercise, K⁺ is transported out of the muscle cells. As the intracellular K⁺
levels fall and extracellular levels rise, motor unit activation
decreases leading to a decrease in muscular force output. Caffeine
delays the outflux of K⁺ from muscle cells, which

delays the onset of skeletal muscle fatigue, allowing an athlete to
maintain motor unit force for a longer period of time. The half-life of
caffeine is 4 to 6 hours, with the mean time to reach peak plasma
concentration between 30 to 60 minutes.

Caffeine has been studied for the past century. It is
used in combination with aspirin and ephedra to form a potent fat and
weight loss supplement. Because caffeine spares muscle glycogen, it has
been used to increase aerobic and anaerobic endurance. As a CNS
stimulant, caffeine can improve concentration. Most of the studies
examining the effects of caffeine involve doses of caffeine ranging
roughly from 2.0 to 9.0 mg/kg/day to 250 to 750 mg/day. For comparison,
a 6-oz cup of coffee contains 100 mg, an 8-oz can of soda contains 40
mg, and a single tablet of Vivarin has 200 mg. The source of caffeine
does matter in determining the efficacy. Studies have compared the
effect of caffeine tablets versus coffee on performance. Caffeine from
coffee causes a significantly decreased ergogenic effect. Caffeine
pills release much more epinephrine and induce a greater rise in serum
free fatty acids and a greater increase in time until exhaustion during
exercise. Caffeine ingested from consumption of coffee is much less
ergogenic. How the dosage of caffeine is divided is also important in
determining its effects. Because the P450 enzymes in the liver
metabolize caffeine, there is a caffeine level at which this pathway
becomes saturated, and the effects of caffeine diminish at 9 mg/kg. It
has been found that taking 3 to 5 mg/kg of caffeine prior to exercise
and then in repeated smaller doses of 1 to 2 mg/kg during prolonged
aerobic exercise is more effective.

There is clear evidence that caffeine improves
performance in endurance events, with many studies supporting the use
of caffeine as an ergogenic aid in swimming, cycling, skiing, running,
and other sports. It has been shown to decrease race times from
marathons to short sprints lasting less than 90 seconds. Caffeine has
even been shown to increase maximum power generated by cyclists in
6-second sprints.

Caffeine use has been shown to cause anxiety, heart
palpitations, trembling, nervousness, and facial flushing. These
adverse effects are usually dose-related; more side effects were
reported when subjects consumed greater than 6 to 9 mg/kg body weight.
Two to three cups of coffee provide about 5 mg/kg body weight of
caffeine. The lethal half-dose of caffeine is 150 to 200 mg/kg body
weight, roughly 100 cups of coffee. Acute caffeine toxicity can cause
hematemesis, hyperventilation, hyperglycemia, ketonuria, hypokalemia,
metabolic acidosis, and cardiac arrhythmias. Tolerance to caffeine can
appear after 4 to 5 days, meaning an athlete must increase his or her
dose to get the same desired effect. It only takes 3 days of caffeine
use for subjects to develop dependency and experience withdrawal
symptoms after stopping it. The withdrawal symptoms from caffeine
include mood shifts, headaches, tremors, and fatigue. Symptoms can last
anywhere from 12 hours to 7 days. Even though caffeine is considered a
mild diuretic, studies showed no change in serum electrolyte levels, no
increased dehydration, no change in core temperature, and no change in
renin concentration.

Ephedra sinica, also known as Chinese ephedra, and Ephedra vulgaris,
also known as Ma Huang, have been around for 5,000 years. In ancient
Chinese medicine, ephedra was known to relieve respiratory ailments. It
was mixed into herbal teas and cold medicines. Ephedra is a stimulant
that mimics the effects of norepinephrine and epinephrine. The sale of
ephedra alone has been prohibited because it can be altered to make
methamphetamine (also called “speed,” “crystal meth,” or “crank”).

Ephedra is a nonselective sympathomimetic drug. It affects β₁-, β₂-, and α-adrenergic receptors. By stimulating the β₂-receptors,
ephedra increases lipolysis—thereby increasing circulating levels of
free fatty acids—increases heart rate, increases cardiac contractility,
and increases bronchodilation. Ephedra also has a thermogenic effect;
it increases resting metabolic rate, increases calorie expenditure, and
decreases appetite.

Ephedra has been touted as a powerful weight loss
supplement, with more than 50 studies of its effects on body fat loss.
Ephedra causes an average of 1.0 kg of body fat loss per month compared
with placebo. There were no long-term studies of the effects of ephedra
because all of the weight loss studies were less than 6 months in
length. Doses of ephedra ranged from 25 to 120 mg/day. There was a
dose-related effect with ephedra: the higher the dose, the greater the
average fat loss per month. Although ephedra is a potent fat loss agent
by itself, studies have shown that, in combination with caffeine, its
efficacy increases. No studies have shown that supplementation with
ephedra improves strength, power, reaction time, speed, aerobic
capacity, or anaerobic capacity, except for a few studies that combined
ephedra and caffeine and found increased endurance.

Subjects consuming ephedra showed a wide variety of side
effects, ranging from heart palpitations, hypertension, nervousness,
anxiety, hyperthermia, headaches, and cardiac arrhythmias. Most of
these adverse effects happen with great frequency at higher doses. Side
effects of ephedra were minimized when subjects consumed less than 60
mg/day, and the adverse effects stopped after subjects discontinued
ephedra use. The FDA has reported 800 adverse incidents from ephedra
use, although most of these events occurred when people consumed doses
in excess of the recommended daily dose. There have been 284 serious
adverse events, including 5 deaths, 5 heart attacks, 11 strokes, and 4
seizures. Half of these serious adverse events occurred in people under
the age of 30 years. One study showed that ephedra-containing
supplements accounted for 0.82% of all supplement sales but caused 64%
of supplement adverse reactions.

Glucosamine is an amino monosaccharide found in human
tissues, including cartilage. It is formed by adding an amino group to
glucose. It is the primary building block of proteoglycans and causes
increased production of hyaluronic acid. Chondroitin sulfate is a mixed
group glycosaminoglycans found in articular cartilage. They are two
major compounds found in healthy cartilage. Carbon-14 tagging of
ingested glucosamine revealed that 4 hours after ingestion, there is
increased proteoglycan synthesis and increased human chondrocyte gene
expression in vitro.

There have been more studies examining the effects of
glucosamine supplementation alone or in combination with chondroitin
sulfate than chondroitin sulfate by itself. Glucosamine and chondroitin
sulfate supplementation have been shown to produce symptomatic relief
from osteoarthritis, decrease the progression of knee osteoarthritis,
and limit joint space narrowing. Though studies have shown these
results over years, glucosamine and chondroitin sulfate users show
improvement even at 2 weeks, having an increase in function and a
decrease in articular stiffness.

The safety of glucosamine and chondroitin sulfate is
excellent. In all of the studies done on glucosamine and chondroitin
sulfate, there were no serious side effects. The placebo groups had the
same incidence of side effects as the treatment groups.

The RDA is defined as the minimum amount of a particular
nutritional substance—vitamin, mineral, or macronutrient—that a person
must consume in order to survive. When it comes to protein, the RDA is
based on the level required to maintain equilibrium in nitrogen
balance. The RDA was first established in the 1970s and has not been
revised since 1989, nearly 15 years ago. The RDA for protein is 0.8
g/kg body weight/day. The RDA specifically states that it does not
recognize an additional protein requirement for athletes or people who
exercise. According to the RDA, a sedentary, 90-year-old man who weighs
140 pounds requires more protein each day than a 130-pound female
college soccer player in the middle of her sports season. This example
clearly points out the shortcomings of the RDA for protein.

One hour of aerobic exercise at 55% to 67% of VO_2max
leads to a 16% to 25% increase in protein oxidation. During exercise,
protein is broken down at a much higher rate than when an individual is
at rest. If the body’s increased protein needs are not met, the body
simply extracts the required protein from itself, from what it
considers nonessential sources. The brain, heart, and vital organs are
all deemed essential, but the body does not understand why an athlete
needs additional muscle mass on his or her arms or legs, so it
catabolizes it. Nitrogen balance is a way of accessing whether or not a
person’s body is getting enough protein. A negative nitrogen balance
means an individual needs to consume more protein, whereas a positive
nitrogen balance means the body is getting enough protein to build new
muscle. However, there is a level at which extra dietary protein stops
being useful to the body. A study examining how strength training
changes dietary protein requirements showed that, only after 1 week,
athletes consuming 1 g/kg body weight/day had a negative nitrogen
balance. Studies have shown that athletes need at least 1.4 g/kg body
weight/day and may need as much as 2.0 g/kg body weight/day.

The longer the duration of exercise and the greater the
intensity, the more protein is used and the higher one’s dietary needs.
Resistance training increases protein synthesis in the postexercise
period by 50% to 100%. There is also an increased rate of amino acid
transport and increased blood flow into skeletal muscles. Skeletal
muscle protein synthesis is elevated at least 50% in the 48 hours
following exercise, resistance training in particular. Peak muscle
growth and protein synthesis are seen primarily in the first 3 hours,
where there can even be a 100% increase in protein synthesis. A study
of 60- to 90-year-old men and women showed that the combination of
protein supplementation and resistance training produced significantly
greater increases in muscle strength and LBM than just resistance
training alone. Another study found that 4 weeks of strength training
while taking additional protein supplementation produced greater
increases in LBM than just strength training alone.

Whenever there is a discussion about athletes consuming
protein loads at levels far greater than the RDA, the topic of kidney
function is raised. There is the misconception that a high-protein diet
leads to or causes kidney failure. This logic comes from the fact that
patients with chronic kidney disease and kidney failure are put on
low-protein diets. However, no study looking at protein loads greater
than the RDA has reported any side effects or health dangers. A review
of the literature shows there is no evidence that high-protein diets in
healthy men and women with normal kidney function leads to kidney
failure.

The BCAAs are three essential amino acids—leucine,
isoleucine, and valine. They make up 20% of the total amino acids found
in the body. They are found in high quantities in actin and myosin, the
two most abundant proteins in the body. Actin and myosin are skeletal
muscle proteins, which make up 65% of all the protein in the body.
BCAAs are present in most proteins (e.g., fish, chicken, red meat,
eggs, and milk). For vegetarians, BCAAs are present in smaller amounts
in nuts, legumes, and some vegetable and grains. The RDA has set the
minimum daily allowance of BCAAs at 3 g/day. Most supplements supply
between 5 to 10 g/day. During exercise, amino acids account for about
10% to 15% of the fuel used, with fats and carbohydrates providing the
bulk. However, after a 90-minute strength training session, the
concentration of BCAAs in muscle drops by 24%. This is because
oxidation of BCAAs increases by 85% to 500% during exercise, depending
on the level of intensity and the duration of the activity. This means
that exercise breaks down a significant amount of BCAAs. The theory is
that supplementation with BCAAs would improve postworkout recovery,
limiting exercise-induced protein degradation, and create an increase
in lean muscle mass. Another interesting effect of BCAAs is their
relationship to the amino acid tryptophan. Many people know tryptophan
as the substance in turkey that makes one tired after the Thanksgiving
Day meal. An increase in the ratio of plasma tryptophan to BCAAs causes
an increase in fatigue. This occurs because low levels of BCAAs enhance
the uptake of tryptophan, which is used to make serotonin, and
increased serotonin levels lead to increased tiredness and central
fatigue.

In septic patients, total parenteral nutrition given
with BCAAs increased mortality, showed less overnight skeletal muscle
breakdown, and increased LBM during hospitalization when compared with
total parenteral nutrition without BCAAs. However, other studies
examining BCAA supplementation in the critically ill did not show any
increased

benefit.
Leucine supplementation alone has been shown to stimulate greater
protein synthesis than placebo. In rats, leucine administration caused
a greater increase in lean muscle mass. Adding BCAAs to postworkout
drinks containing a combination of carbohydrates and proteins
immediately postexercise led to a reduction in serum cortisol levels,
increased protein synthesis, and decreased muscle breakdown. BCAA
supplementation has also been associated with an increase in LBM, a
decrease in skeletal muscle degradation, and a decrease in body fat.
BCAA supplementation can also aid performance and improving run times.
Moreover, BCAA supplementation during aerobic endurance events—such as
soccer matches, marathons, long distance cycling, and long distance
swimming—can reduce fatigue and delay depletion of muscle glycogen.

BCAAs have not shown any adverse reactions or increased
side effects when compared with a placebo. A review of the literature
has no mention of any health risks to BCAA supplementation.

Glutamine is used by the hair follicles, the immune
system, the liver, the gastrointestinal tract, the brain, and, of
course, skeletal muscles. Glutamine is one of the major sources of fuel
used by the gastrointestinal tract, accounting for close to 40% of
total body utilization of glutamine. In the brain, glutamine is used to
build neurotransmitters. For athletes, the most important function of
glutamine is on skeletal muscle. During times of high levels of
physiologic stress, like the end of and after an intense training
session, the body has high levels of glucocorticoids. Glucocorticoids
are catabolic substances, increasing protein and muscle breakdown.
Glutamine has a muscle protein-sparing effect and counteracts the
actions of glucocorticoids to some degree. Glutamine increases the
amount of amino acids released from skeletal muscle, reducing muscle
protein degradation. It also increases the rate of muscle glycogen
resynthesis. By repleting muscle glycogen stores more quickly,
glutamine aids in helping the body recover from intense exercise at a
faster rate. During training, glutamine helps in delaying fatigue by
buffering skeletal muscle from metabolic acidosis. It does this by
being converted to α-ketoglutarate and an ammonium ion (NH⁴⁺).
This serves to buffer the pH of the skeletal muscle, since decreasing
pH leads to metabolic acidosis and reduces the body’s ability to
perform.

In times of extreme stress, the body needs additional
supplementation with glucose. Burn patients, surgical patients, septic
patients, and any patient who needs increased wound healing have all
been shown to catabolize skeletal muscle to use the amino acids
elsewhere in the body. When the body is prioritizing where it needs
amino acids, preserving muscle mass is not high on the list.
Administration of glutamine to these patients increases the rate of
wound healing while decreasing the breakdown of skeletal muscle. This
is important to athletes because overtraining and prolonged exercise
create an environment of extreme stress in the body that can lead to
increases in muscle breakdown and injury. By supplementing with
exogenous glutamine, an athlete can aid in his or her body’s healing
process. Glutamine plays a role in helping the immune system function
and affects lymphocyte function. In a study that examined the effect of
glutamine supplementation on upper respiratory infections in athletes,
significantly fewer infections developed in runners who received
glutamine.

Data do not seem to support glutamine having an
ergogenic effect on strength training performance. Glutamine acts as a
substrate for gluconeogenesis in the liver, increasing muscle glycogen
stores after prolonged exercise. This is especially useful to endurance
athletes in the postworkout recovery period.

There have been no reported side effects in any of the
studies examining glutamine supplementation. Also, there have been no
case reports of any adverse effects from using glutamine.

The concept behind carbohydrate supplementation in
conjunction with exercise is that exercise depletes muscle glycogen and
carbohydrate ingestion repletes those same stores. Decreased muscle
glycogen means decreased performance, decreased isokinetic force,
decreased isometric strength, and increased muscle weakness.
Carbohydrate supplementation has been shown to increase the amount of
work performed and to increase the duration of aerobic exercise. Taking
carbohydrates in the postworkout state causes a spike in blood sugar,
which begins a cascade of effects leading to increased muscle recovery
and growth. The rapid rise in blood glucose releases a corresponding
insulin spike. The insulin spike produces an increase in growth
hormone, and this creates an anabolic environment for muscle growth and
glycogen repletion.

Studies show that carbohydrate supplementation aids in
muscle recovery and glycogen stores, but strength performance has not
always been found to be increased. Other studies show that carbohydrate
ingestion improves aerobic performance in those training for more than
60 minutes.

Carbohydrate consumption was not found to be associated
with any negative side effects. None of the studies examined discussed
any increased health risks from carbohydrates.

The carbohydrate-protein (CHO/PRO) combination refers to
a liquid concoction that provides an athlete with calories from both of
these fuel sources. The idea is that there is a synergistic effect in
combining the two nutrients. Carbohydrate ingestion repletes glycogen
stores and creates an anabolic environment through insulin spikes.
Protein increases muscle growth and decreases the rate of muscle
breakdown. With the CHO/PRO combination, the rise in insulin
preferentially drives glucose and amino acids into muscle cells.

In one study examining insulin and hGH levels after
supplementation of placebo, carbohydrate, or CHO/PRO supplement, the
CHO/PRO had a statistically significant greater rise in both insulin
and hGH. A combination of 6 g of essential amino acids and 35 g of
carbohydrates after intense resistance training created a 10-fold
increase in insulin levels, a 3-fold increase in amino acid levels in
skeletal muscle, and a 3½-fold increase in protein synthesis, compared
with placebo and carbohydrates only groups. The postworkout timing of
when to take the CHO/PRO supplement is also important, because
immediately after exercise is the time when net protein turnover is
greatest. The insulin spike climbs and peaks around 90 minutes and then
declines over several hours. The best time to ingest the CHO/PRO
combination is immediately after exercise and then around 90 to 120
minutes postworkout.

As reported previously, carbohydrates and proteins have no serious reported side effects or health risks.

Athletes need fat in their diet for hair, skin, muscle,
brain, and nervous tissue development. Fat protects the body’s vital
internal organs. Fat can also be an important source of energy to the
body during exercise, especially when muscle glycogen stores get
depleted. It has been theorized that supplementation with healthy
unsaturated fats might improve athletic performance. The idea is that
if an athlete ingested a fat source before or during exercise, then the
body might preferentially use the fats as the primary fuel source and
delay using muscle glycogen. The longer the body spares muscle
glycogen, the longer the athlete can train or race before fatigue
begins.

When compared with studies looking at the effects of
carbohydrate and protein supplementation in athletes, there is not
nearly as much research with fats, and the studies that have been done
have yielded mixed results.

Several of the studies reported that the athletes
consuming the high-fat diets initially had some gastrointestinal
symptoms that included primarily diarrhea, steatorrhea, and nausea. No
other side effects were reported, and many of the side effects
diminished as the subjects remained on the diet for a longer period of
time.

When looking at the effects of water on athletic
performance, it is best to look at the effects of hypohydration.
Failure to replace fluid losses leads to exhaustion ineffectiveness.
For every 1% of body weight loss, there is a 0.1° to 0.2°C rise in core
temperature, increasing the risk for hyperthermia. That small 1% loss
of body weight due to dehydration has been shown to increase heart
rate, decrease muscle strength, and decrease cardiovascular endurance.

Dehydration has a documented effect on strength
performance and has been associated with decreased systolic blood
pressures, increased heart rates, increased urine specific gravity, and
increased rectal temperatures. Dehydration decreases endurance
performance and has adverse effects on cognitive performance, including
impaired arithmetic ability, worsened short-term memory, and decreased
visuomotor tracking.

Although dehydration has negative effects on exercise
performance, too much hydration can lead to serious consequences as
well. Hyperhydration can lead to hyponatremia. Symptomatic hyponatremia
can cause disorientation, confusion, nausea, emesis, and muscle cramps.
Severe cases can lead to seizures, coma, or death. These effects can
happen during an athletic event and even up to 6 hours after
competition.

As a CNS stimulant, amphetamines increase blood
pressure, increase maximum heart rate, increase metabolic rate, and
increase the serum concentration of free fatty acids by the endogenous
releasing of catecholamines. This increase in free fatty acids spares
muscle glycogen, thereby delaying the onset of fatigue.

Amphetamines have well-established ergogenic effects.
There is a long history of amphetamines use to enhance performance of
elite cyclists, including increases in quad strength, sprint
acceleration, anaerobic capacity, maximum heart rate, and time until
exhaustion. Increased muscle strength, increased time until fatigue,
increased lactic acid levels at maximum exercise, increased heart rate,
decreased appetite, and an increased baseline metabolic rate have also
been reported.

Amphetamines are addictive and have high potential for
abuse. Their side effects include headaches, dizziness, insomnia,
anxiety, hallucinations, and mental confusion. Chronic amphetamine
users are at increased risk of hypertension, stroke, arrhythmias, and
ulcers. Athletes injecting amphetamines are also at increased danger of
HIV, hepatitis B, and hepatitis C.