Download Ephedrine and Other Stimulants As Ergogenic Aids

Ephedrine and Other Stimulants
As Ergogenic Aids
Amy Miller Bohn, MD, Morteza Khodaee, MD, and Thomas L. Schwenk, MD*
Address
*Department of Family Medicine, 1500 East Medical Center Drive,
L2003 Womens, Box 0239, Ann Arbor, MI 48109, USA.
E-mail: [email protected]
Current Sports Medicine Reports 2003, 2:220–225
Current Science Inc. ISSN 1537-890x
Copyright © 2003 by Current Science Inc.
Several recreational, prescription, and illicit drugs have
psychotropic effects that may be perceived to be ergogenic.
The ephedra alkaloids have received recent attention for their
wide use by athletes and their potential serious side effects,
despite the lack of evidence regarding any ergogenic or performance benefit. Some prescription drugs (eg, methylphenidate
and bupropion) raise complex issues regarding their appropriate therapeutic use in athletes. Recreational drugs, some of
which are illegal (eg, cocaine), are commonly used by athletes
and cause a wide range of potentially ergolytic effects. In total,
these drugs are important for their frequent use, the
frequency with which they are mentioned in the media, and
their potential for causing significant adverse effects.
Introduction
A wide range of recreational, prescription, and illicit drugs
have psychotropic effects that are ergogenic, or are perceived
to be ergogenic by athletes [1]. Some are notable for their
nearly ubiquitous use, such as alcohol; others are notable
because they are the subject of intense media coverage of
tragedies and complications related to their use, such as
ephedrine use in football players, or the use of amphetamines by US Air Force combat pilots. Some psychotropic
drugs or agents (eg, nicotine) are not used for ergogenic purposes, and others (eg, tricyclic antidepressants) are little used
at present. β-Blockers have psychotropic effects, such as
reducing the physiologic manifestations of performance
anxiety through catecholamine blockade, but are not considered ergogenic in the usual use of the word (although
they are banned in sports for which reduced muscle tremor
is ergogenic, such as archery). This article reviews psychotropic drugs that are commonly used, that have significant
potential or putative ergogenic effects, are particularly prominent with regard to regulation, or are late-breaking additions to the never-ending list of substances used by athletes
who seek to gain a competitive edge.
Ephedrine
Ephedra alkaloids are popular components of many nutritional supplements, with approximately 3 billion doses sold
in 1999 [2]. They are found in several plant species, including
Ephedra sinica, E. intermedia, and E. equsetina, collectively
known as Chinese ephedra or ma huang, and Sida cordifolia
[3••,4]. Purified forms of these substances include ephedrine,
pseudoephedrine, norephedrine, methylephedrine, norpseudoephedrine, and methylpseudoephedrine. Phenylpropanolamine is a synthetic compound functionally similar to the
ephedra alkaloids in effect and use.
Epidemiology
One study of commercial fitness center clients reported ephedrine use within the past 3 years in 109 of 511 subjects, which
would extrapolate to a national use by 2.8 million American
recreational athletes [5]. A National Collegiate Athletic Association (NCAA) study of the drug and supplement use habits
of 21,000 college students from 713 NCAA member institutions in 2001 [6] showed an increase in ephedrine use from
3.5% to 3.9% compared with rates in 1997. Men's lacrosse
(5.5%) and women's gymnastics (8.3%) had the highest rate
of ephedrine use among NCAA athletes. The major reasons to
use supplements as reported by athletes are improved athletic
performance (27.3%), improved physical appearance
(27.3%), and weight control (19.7%). More than half of
these college athletes started using nutritional supplements
before finishing high school.
Pharmacology and clinical uses
Ephedra alkaloids are sympathomimetic agents that act as
both α and β adrenergic agonists, and enhance the release of
norepinephrine from sympathetic neurons [7]. Ephedra alkaloids cross the blood-brain barrier and are a potent central
nervous system (CNS) stimulator. Functionally, the ephedra
alkaloids are similar to amphetamines, although weaker. The
relative balance of α and β receptors determines their net
effect. Sympathetic stimulation can cause excitatory effects in
some tissues, and inhibitory effects in others. Stimulation of α
receptors in vascular smooth muscle leads to contraction and
vasoconstriction. β1 receptors, primarily found in cardiac tissue, may lead to increased heart rate and myocardial strength
when stimulated. Stimulation of β2 receptors in bronchial
smooth muscle causes bronchodilatation, and vasodilatation
in skeletal muscle [8].
Ephedrine and Other Stimulants As Ergogenic Aids • Bohn et al.
Clinically, ephedrine has been used in the past for the
treatment of asthma, but has no current common therapeutic use. Pseudoephedrine can be found in many prescription
and over-the-counter preparations (used mostly for the treatment of congestion) that may be associated with respiratory
infections or allergies. Until its recent voluntary removal
from the market because of reports of increased risk for
stroke in women, phenylpropanolamine was also used similarly to pseudoephedrine and in over-the-counter diet pills.
Ephedra alkaloids have been used for both asthma and allergies in China for more than 5000 years [9].
Ephedrine is excreted largely unchanged in the urine and
the usual elimination half-life is 3 to 6 hours, which can be
prolonged with increased urine pH [10]. Gas chromatography coupled with mass spectrometry of a urine sample is the
standard test for the purpose of detecting unapproved use. A
urine concentration of greater than 10 µg/mL is considered
positive by the NCAA, the International Olympic Committee
(IOC), and the National Football League (NFL). Hair analysis can be valuable as a complement to urinalysis for providing a more accurate history of drug use, but has yet to be
standardized [11].
Athletic applications
With their stimulant properties and sympathomimetic
actions, ephedra alkaloids have been perceived as lending
unfair advantages to athletes when used in supplement form.
Many athletes use substances containing ephedra alkaloids because of perceived benefits of increased energy,
decreased time to exhaustion, and potential thermogenic
properties with increased metabolism, increased fat loss,
and improved muscle strength. Studies investigating the
use of ephedra alkaloids at standard dosages have not supported their perceived performance-enhancing properties.
However, some studies looking at the use of ephedrine
and caffeine together have supported potential ergogenic
effects [12,13•,14–18].
Sidney and Lefcoe [12] studied the use of ephedrine
and the effect on cardiorespiratory endurance, maximal
oxygen uptake, ratings of perceived exertion, lung function,
anaerobic capacity, speed, reaction time, hand-eye coordination, and muscle function. When compared with placebo, there were no statistically significant differences. They
did, however, find that blood pressure and heart rate were
significantly elevated.
DeMeersman et al. [13•] evaluated the effects of ephedrine use on 10 subjects during a cycle ergometer test. They
assessed various cardiorespiratory variables, as well as ratings
of perceived exhaustion and found no statistically significant
advantage for ephedrine use over placebo. Interestingly, their
research was prompted by an IOC investigation of an American athlete who tested positive for ephedrine use from incidental inhaler use for asthma during the 1972 Olympics. He
was forced to return his gold medal based on the assumption
that the ephedrine offered him an unfair advantage, a deci-
221
sion challenged by DeMeersman et al. [13•] on the basis of
this research.
Similar studies have evaluated the potential effects of
pseudoephedrine at both standard doses and doses that are
higher than recommended. Gill et al. [14] evaluated the effect
of a 180-mg dose of pseudoephedrine administered 45 minutes prior to exercise on short-term maximal exercise performance. Subjects completed a series of tests, including
isometric knee extension, bench press at one repetition maximum (1RM) and 70% of 1RM, and a 30-second maximal
cycle ergometry test. Subjects taking pseudoephedrine experienced increased maximum torque during isometric knee
extension, improved peak power during cycle performance,
and improved lung function when compared with placebo.
Bench press tasks and total work during the cycle test were not
significantly changed [14].
Most studies, however, have evaluated pseudoephedrine at
more standard dosages and could not show evidence of performance enhancement. Clemons and Crosby [15] investigated the effects of 60 mg of pseudoephedrine on heart rate,
respiratory exchange ratio, ventilation, oxygen consumption,
respiratory rate, tidal volume, systolic and diastolic blood pressure, total exercise time, core temperature, and ratings of perceived exertion during graded exercise tests with the Bruce
protocol. Their only significant findings were of increased
heart rate during each stage and at 8 minutes of recovery. Gillies et al. [16] also found that pseudoephedrine at a dose of
120 mg did not produce measurable ergogenic effects during
high-intensity exercise of 1 hour duration with cycle ergometry. Bright et al. [17] evaluated heart rate, blood pressure, glucose, and insulin after administration of pseudoephedrine at
60 and 120 mg during submaximal exercise. They found no
significant changes in these variables, but did report an
increased risk of sinus arrhythmias at the 120-mg dose. Finally,
Swain et al. [18] looked at the effects of both pseudoephedrine
and phenylpropanolamine at standard dosages during cycle
ergometry. They found no significant changes for either substance with measurements of VO2max, rating of perceived
exertion, maximal systolic and diastolic blood pressure, heart
rate, or time to exhaustion, with the exception of peak systolic
blood pressure after administration of pseudoephedrine.
In summary, it appears that the isolated use of ephedrine,
pseudoephedrine and phenylpropanolamine at usual dosages has an inconsistent, and probably insignificant, ergogenic benefit for power, endurance, strength, or speed.
A series of studies by Bell et al. and Bell and Jacobs
[19•,20–24] evaluated the effects of ephedrine in combination with caffeine and found the combination to enhance
performance. In a study of 5 mg/kg of caffeine and 1 mg/kg of
ephedrine, administered separately and together, the combination resulted in an increased time to exhaustion and
decreased rating of perceived exhaustion on cycle ergometry
compared with either drug alone or placebo. A quarter of the
subjects experienced nausea and vomiting with exercise after
the combination of caffeine and ephedrine [19•]. Doses as
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Ergogenic Aids
low as 4 mg/kg of caffeine and 0.8 mg/kg of ephedrine in
combination were equally as effective as the higher doses, and
caused fewer gastrointestinal side effects [23]. Similarly, the
combination of 375 mg of caffeine and 75 mg of ephedrine
given prior to a Canadian Forces Warrior Test, a 3.2-km run
wearing a helmet, rifle, webbing, full canteen, back pack, and
combat boots, resulted in significantly faster race times and
higher heart rates [21].
The findings regarding the effect of ephedrine on weight
loss are equivocal. Theoretically, ephedrine can increase metabolic rate and suppress appetite. In a randomized study on
167 subjects, Boozer et al. [25] showed that herbal ephedra/
caffeine (90–192 mg/d) can promote body weight and body
fat reduction. Average weight loss was 5.3 ± 5 kg with herbal
treatment and 2.6 ± 3.2 kg with placebo in a 6-month trial (P
< 0.001). However, the results in less selected populations and
less controlled settings are far less impressive, and the use of
ephedrine for weight loss has been mostly discounted.
Adverse effects
There are serious concerns regarding the safety of supplements containing ephedra alkaloids. In 1994, the Dietary
Supplement Health and Education Act excluded dietary supplements from rigorous US Food and Drug Administration
(FDA) regulation. Because supplements are not considered
therapeutic, they are not held to the same level of rigor in
claiming efficacy and safety as that required of prescribed and
over-the-counter medications [26]. Since the 1994 deregulation, an increasing number of reports of adverse events,
including hypertension, arrhythmias, myocardial infarction,
seizure, cerebrovascular accidents, and death [27], has
prompted the FDA to recommend a limit on the use of ephedra alkaloids of 24 mg/d for no more than 7 days.
In addition to the more serious adverse events described
above, commonly used dosages of ephedrine can cause headache, dizziness, irritability, anxiety, tremor, and psychosis.
Caffeine can augment the adverse cardiovascular and CNS
effects of ephedrine. The deaths of several high school and
college students have been blamed on the use of ephedra
[28]. Acute myocardial infarction (probably secondary to
vasospasm), cardiac arrhythmias, and stroke are the cause of
death in a majority of cases [29–31,32••]. Pre-existing cardiovascular disease is not a prerequisite for adverse events,
and the cardiovascular toxic effects associated with ma huang
are not necessarily dose-dependent [30,31]. Haller and
Benowitz [32••] reviewed 140 reported adverse events from
dietary supplements containing ephedra alkaloids submitted
to the FDA between 1997 and 1999. Using a standardized
rating system to assess causation, 31% of cases were definitely
or probably related to ephedra alkaloids, and 31% were possibly related. Of these two groups, 47% involved cardiovascular events, with the majority related to hypertension (17
cases) and tachycardia or palpitations (13 cases), whereas
18% involved CNS events, with stroke (10 cases) and seizures
(seven cases) being most prevalent; 10 events resulted in
death and 13 in permanent disability.
Many case reports have identified substances containing
ephedra alkaloids as possible causative factors in adverse
events occurring in otherwise healthy young adults. Wooten
et al. [33] reported a case of a 20-year-old man who developed an intracerebral hemorrhage and vasculitis after the
ingestion of “speed” containing ephedrine. Kockler et al.
[34] reported the hospitalization of a 22-year-old man after
seizure-like activity believed to be related to ephedrine
ingestion. Bruno et al. [35] reported three cases involving
patients who developed a cerebrovascular accident believed
to be linked to ephedrine use. Vahedi et al. [36] reported a
case of ischemic stroke in a 33-year-old sportsman after
ingestion of ma huang, and Theoharides [37] reported sudden death of a healthy college student after ingestion of a
ma huang-containing beverage.
In a landmark study, Kernan et al. [38] collaborated
with the FDA and manufacturers of phenylpropanolamine
to evaluate the risk of hemorrhagic stroke associated with
its use. In a case-control study assessing the risk in both
men and women ages 18 to 49 years recruited from 43 US
hospitals, phenylpropanolamine use was an independent
risk factor for hemorrhagic stroke in women. This study
prompted the voluntary removal of phenylpropanolamine
from the market, including the removal of many over-thecounter appetite suppressants and cold remedies.
Ephedrine has been banned by the IOC for years, the
NCAA since 1997, and most recently by the NFL. Recently,
the US armed forces also banned ephedra products from
commissaries and military exchanges worldwide. Ephedracontaining products, including a wide range of weight-loss
products, are not regulated by FDA. Gurley et al. [39] found
dramatic mislabeling and inconsistencies among many
ephedra-containing dietary supplement products. In 1997,
the FDA proposed a limit for ephedrine alkaloids in dietary
supplements of 8 mg per serving within a 6-hour period, or
24 mg/d [27]. The current maximum dose of nonprescription ephedrine is 25 mg, with a maximum daily dose of
100 mg [39].
Athletes are forever searching for the one element that
will give them a competitive edge, but they are often less
clear about the cost they are willing to bear from trying the
many supplements promising to provide them with performance enhancement. Ephedra alkaloids taken alone and at
standard dosages have not been proven to have ergogenic
properties. Not only do athletes risk disqualification at the
elite level when using supplements containing ephedra
alkaloids, they may be risking their lives. Because of recent
highly publicized tragedies, various athletic associations
have focused on further evaluations of the use of these substances and on trying to educate athletes about potential
health risks associated with their use. In September 2001,
shortly after the death of the Minnesota Vikings’ Corey
Stringer, NFL commissioner Paul Tagliabue announced the
league’s ban on ephedrine usage. Year-round random drug
testing was initiated in July 2002 as the NFL became the
first professional league to institute such a ban. Continued
Ephedrine and Other Stimulants As Ergogenic Aids • Bohn et al.
evaluation of the use of these substances is necessary, as is
continued education of athletes, parents, coaches, and
trainers regarding the health risks associated with ephedrine alkaloids.
Amphetamines, Including Methylphenidate
The use of methylphenidate and related amphetamine
stimulants for the treatment of attention deficit and hyperactivity disorder (ADHD) has increased significantly in
recent years, probably due to both increased accuracy of
diagnosis and increased demand by parents for stimulant
treatment [1]. This increased prevalence of use has resulted
in sports and team physicians being faced with an increasing number of athletes asking about its use, regulation, and
effects on athletic performance. In addition, methylphenidate in particular is commonly abused by adolescents,
through crushing tablets for sublingual mucosal absorption, usually for recreational purposes, and this use could
lead to detection during drug testing by regulatory agencies
such as the NCAA.
Amphetamine was synthesized in 1920 and used to
reduce fatigue and increase alertness during World War II. Its
effect on well-rested subjects is unclear, with claims of more
rapid learning of new tasks, and increased physical energy,
confidence, and well-being [40]. Its effects on sleep-deprived
subjects are more clear, and more controversial, with regard to
improved attention deployment, focus, and concentration.
There are several proposed mechanisms, most of which
involve the increased turnover of neurotransmitters such as
dopamine and norepinephrine. It may be ergogenic in shortterm power performance, possibly through tolerance of
longer periods of anaerobic metabolism, although controlled
data are scant. What is more clear is the increased risk of serious, sometimes fatal, side effects of amphetamine use, including heatstroke due to shunting of blood to the core and away
from skin. Impaired judgement may cause the athlete to compete while injured, as well as possibly harming other athletes
through inappropriate behavior. All amphetamines are
banned by the IOC, and the NCAA requires substantial and
current documentation of the medical indication for their
use, with concern that it may be inappropriately justified by
an inaccurate, falsified, or outdated diagnosis of ADHD. The
recent release of a new, nonstimulating medication for the
treatment of ADHD will raise new questions about the appropriate approach to ADHD in athletes, as well as stimulate
studies assessing the possible ergogenic effect of this and
future new medications.
223
release [40,41]. Withdrawal produces fatigue and depression.
It is most notable for distorting the user’s perception of reality; in an athlete, for example, the perception of increased
levels of performance, decreased fatigue, and increased
strength, despite objective measures to the contrary [42]. Its
vasoconstrictive effect can be fatal through the induction of
cardiac arrhythmias and coronary artery ischemia [43], and it
is banned by both the NCAA and IOC, including its use as a
local anesthetic.
Bupropion
Bupropion is an antidepressant without serotoninergic or
noradrenergic effect that is presumed to act through blockade
of dopamine reuptake [41]. However, bupropion and its
metabolites are actually fairly weak inhibitors of dopamine,
as well as serotonin and norepinephrine, so its actual mechanism of action is unclear. Studies of its clinical pharmacology
are conflicting and equivocal. It is believed to have a stimulating effect through its dopaminergic blockage, and presumably
for this reason was recently banned by the IOC. It is often
used in adolescents with a dual diagnosis of ADHD and unipolar depression, because it is perceived to have a beneficial
additive effect in ADHD, again because of its possible dopaminergic effect. The IOC ban may also be related to the fact that
bupropion can have an anxiolytic effect for athletes involved
in shooting and archery, as well as because other serotoninergic and noradrenergic antidepressants may be banned for certain sports and by certain sports federations because of their
anxiolytic effect. Because the use of any stimulant in patients
with ADHD, such as methylphenidate, has come under new
and more intense scrutiny, bupropion use may be subject to
more intense investigation by sports federations and authorities for this reason as well. There is no known ergogenic
benefit from the use of bupropion with regard to strength or
endurance exercise.
Conclusions
The actual ergogenic benefits of ephedrine, methylphenidate
and other amphetamines, cocaine, and bupropion are
unclear, but all are banned or suspect to varying degrees and
by different sporting federations and associations. This discrepancy between actual benefit and banned status highlights
the difficulty sports physicians have in advising athletes, parents, coaches, and athletic administrators about the proper
approach to monitoring, education, and testing for these
medications. As is true for the approach to many potential
ergogenic substances, good judgement and up-to-date information are essential to appropriate decisions and guidance.
Cocaine
Cocaine has been used by soldiers since the late 1800s to
decrease fatigue, but unlike amphetamines, it currently has no
legitimate medical use except as a local anesthesia for nasolaryngeal procedures. Its recreational use is widespread, and it is
highly addictive, with its effect mediated through dopamine
Addendum
At the time this manuscript went to press, Major League Baseball proposed a ban on the use of ephedrine by certain minor
league baseball players. The ban was proposed because of
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Ergogenic Aids
concerns about the highly publicized death of a major league
baseball player, possibly due to the vasoconstrictive and heat
intolerance effects of ephedrine. The FDA was also exploring
restrictions on the use and marketing of ephedrine by the
general public, and commissioned a meta-analysis of the risks
and benefits of ephedrine [44]. There will likely be continued
active discussion of ephedrine and its adverse effects, and
readers should seek up-to-date information in making appropriate decisions about its use or potential ban.
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