Sports Med 2004; 34 (13): 871-889

REVIEW ARTICLE 0112-1642/04/0013-0871/$31.00/0

 2004 Adis Data Information BV. All rights reserved.

Caffeine and Ephedrine

Physiological, Metabolic and Performance-Enhancing Effects
Faidon Magkos and Stavros A. Kavouras
Laboratory of Nutrition and Clinical Dietetics, Department of Nutrition and Dietetics, Harokopio
University, Athens, Greece

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 871
1. Use in Sports and Legislation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 872
1.1 Caffeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 872
1.2 Ephedrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873
2. Performance Enhancement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874
2.1 Caffeine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874
2.2 Ephedra Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 875
2.3 Caffeine-Ephedrine Mixtures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 876
3. Hormonal Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 879
4. Substrate Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880
5. Cardiovascular Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 882
6. Pulmonary Function and Gas Exchange . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883
7. Psychophysiological Correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 885

Abstract Preparations containing caffeine and ephedrine have become increasingly

popular among sportspersons in recent years as a means to enhance athletic
performance. This is due to a slowly accumulating body of evidence suggesting
that combination of the two drugs may be more efficacious than each one alone.
Caffeine is a compound with documented ergogenicity in various exercise modal-
ities, while ephedrine and related alkaloids have not been shown, as yet, to result
in any significant performance improvements. Caffeine-ephedrine mixtures, how-
ever, have been reported in several instances to confer a greater ergogenic benefit
than either drug by itself. Although data are limited and heterogeneous in nature to
allow for reaching consensus, the increase in performance is a rather uniform
finding as it has been observed during submaximal steady-state aerobic exercise,
short- and long-distance running, maximal and supramaximal anaerobic cycling,
as well as weight lifting. From the metabolic point of view, combined ingestion of
caffeine and ephedrine has been observed to increase blood glucose and lactate
concentrations during exercise, wheareas qualitatively similar effects on lipid
fuels (free fatty acids and glycerol) are less pronounced. In parallel, epinephrine
and dopamine concentrations are significantly increased, wheareas the effects on
norepinephrine are less clear.
With respect to pulmonary gas exchange during short-term intense exercise, no
physiologically significant effects have been reported following ingestion of
caffeine, ephedrine or their combination. Yet, during longer and/or more demand-
ing efforts, some sporadic enhancements have indeed been shown. On the other
872 Magkos & Kavouras

hand, a relatively consistent cardiovascular manifestation of the latter preparation

is an increase in heart rate, in addition to that caused by exercise alone. Finally,
evidence to date strongly suggests that caffeine and ephedrine combined are quite
effective in decreasing the rating of perceived exertion and this seems to be
independent of the type of activity being performed. In general, our knowledge
and understanding of the physiological, metabolic and performance-enhancing
effects of caffeine-ephedrine mixtures are still in their infancy. Research in this
field is probably hampered by sound ethical concerns that preclude administration
of potentially hazardous substances to human volunteers. In contrast, while it is
certainly true that caffeine and especially ephedrine have been associated with
several acute adverse effects on health, athletes do not seem to be concerned with
these, as long as they perceive that their performance will improve. In light of the
fact that caffeine and ephedra alkaloids, but not ephedrine itself, have been
removed from the list of banned substances, their use in sports can be expected to
rise considerably in the foreseeable future. Caffeine-ephedra mixtures may thus
become one of most popular ergogenic aids in the years to come and while they
may indeed prove to be one of the most effective ones, and probably one of the
few legal ones, whether they also turn out to be one of the most dangerous ones
awaits to be witnessed.

Athletes have always been seeking the competi-
tive edge to improve performance and win.[1] Dieta-
ry manipulations remain one viable alternative for
achieving this goal, especially among elite athletes
who share a favourable genetic endowment and train
at the limit of what can be considered sustainable.[2]
Such attempts are clearly evident in the anecdotal
fad diets of ancient Greek athletes,[3] as well as in the
contemporary dietary practices during training and
competition for virtually any kind of sport.[4] Along
this line, the field of ergogenic aids has expanded
tremendously in recent years and numerous such
compounds, including potential energy sources, me-
tabolites, recovery aids and drugs, are currently
available alone or in combination and promise en-
hanced endurance, power, strength and speed.[5-7]
Among the various ergogenic aids, only a few
have scientifically documented efficacy; rather,
most are used by athletes on the basis of personal
testimonies of unknown truthfulness and anecdotal
reports of questionable validity.[5-7] In addition,
some formulations may carry significant risks of
adverse health effects[8] and their use is tightly regu-
lated or even completely banned from sports.[9] One
exception is caffeine, and more recently, the combi-
nation of caffeine with ephedra alkaloids.[10] The
purpose of this article is to provide an overview of
the acute effects of combined caffeine plus ephe-
drine ingestion on several parameters of athletic
performance and also to discuss some of the meta-
bolic and physiological effects of such drug prepara-
tions during exercise in humans.
1. Use in Sports and Legislation1
1.1 Caffeine
Caffeine consumption depends on many factors,
such as natural source, age, sex, nutritional status,
fitness level, peer behaviour and habituation.[11] Use
of caffeine in sports is mainly driven by its per-
ceived ergogenic efficiency, but caffeine is also
inexpensive, has little or no acute adverse effects on
health, and is a socially acceptable drug.[12] Approx-
imately 27% of Canadian high-school students[13]

1 At the time this review was written, the proposed new global list of banned substances had not been drawn up. The
new list is now available at the World Anti-Doping Agency (WADA) website: the World Anti-Doping Code – the 2004
Prohibited List – International Standard (http://www.wada-ama.org/docs/web/standards_harmonization/code/
list_standard_2004.pdf). Caffeine, pseudoephedrine and phenylpropanolamine have been removed from the list, while
ephedrine use remains restricted with a 10 mg/L urinary concentration limit.

 2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (13)
Caffeine-Ephedrine Mixtures and Exercise
and US adolescent athletes[14] have been reported to
make use of caffeine for the specific purpose of
improving performance. Furthermore, 68% and
64% of >2000 US college-student athletes surveyed
in 1985 and 1989, respectively, consumed the drug
but claimed to do so for social reasons only.[15] In
competitive sports, there is only one described inci-
dence of the use of caffeine suppositories by the US
Cycling Team in the 1984 Olympic Games,[16] while
disqualification cases due to caffeine abuse are ex-
tremely scarce.[17] For instance, in two recent doping
cases, a US sprinter was stripped of a bronze medal
in the 60m at the 1999 World Indoor Championships
after a positive caffeine test and a female runner
from Suriname lost her gold medal in the 800m at
the 2003 Pan American Games over the same of-
fence.[18] It is believed, however, that use of stimu-
lants in general[19] and caffeine in particular[20,21]
among both professional and amateur athletes is
much more widespread.
Until recently, caffeine was a restricted com-
pound in sports, with a 12 mg/L urinary concentra-
tion limit set by the International Olympic Commit-
tee (IOC).[18,22] However, oral doses up to 9 mg/kg
ingested approximately 1 hour prior to exercise re-
sult in postexercise urine levels that are generally
below the IOC’s cut-off point,[23,24] while the likeli-
hood to exceed 12 mg/L increases significantly with
higher caffeine doses, e.g. 13 mg/kg.[24] Fear that the
IOC limit in urine might be violated has probably
kept consumption of caffeine by athletes at general-
ly low and safe amounts. Amazingly, however, the
drug is about to be taken off the proposed new
global list of banned substances, to be drawn up by
the World Anti-Doping Agency.[18] The usefulness
of the IOC cut-off has been questioned several times
in the past[21,25] and caffeine use by athletes has
repeatedly given rise to significant ethical con-
cerns.[21,25,26] The decision of sport governing bodies
to legalise caffeine, however, is a diametrically op-
posite response to the concerns of the scientific
community and seems hardly logical. In light of this
development, use of caffeine among sportspersons
can be expected to rise considerably in the foresee-
able future.
It is also important to note that many athletes
perceive the ergogenic effects of a given substance
in a ‘linear’ fashion, i.e. the greater the dose the
 2004 Adis Data Information BV. All rights reserved.
873
greater the benefit. It would not be surprising, there-
fore, if some individuals resort to consuming much
larger amounts of caffeine than the recommended
‘optimum’ dose, which lies between 3 and 6 mg/
kg.[12,27] Nevertheless, plasma caffeine concentra-
tions rise in a dose-dependent manner at rest and
during exercise, and an oral dose of 9 mg/kg results
in peak plasma levels of approximately 70–80 µmol/
L.[28] This is just below 100 µmol/L, which is con-
sidered the upper limit above which caffeine’s me-
tabolism saturates (although saturation may occur at
even lower concentrations)[29] and is approximately
2.5-fold lower than the toxic range in humans (i.e.
200 µmol/L).[30] Unrestricted use of caffeine by
athletes may result in consumption of multi-fold
higher doses, and one cannot rule out the possibility
of manifestation of serious acute adverse health
effects, especially among caffeine-naive individu-
als.
1.2 Ephedrine
Ephedrine and related compounds (pseu-
doephedrine and phenylpropanolamine) are struc-
turally similar to amphetamines; they are widely
used alone, or in combination with caffeine, as
weight loss adjuncts or ‘fat burners’ among both
athletes and non-athletes.[31-33] A recent meta-analy-
sis of published studies concluded that such prepara-
tions may indeed be effective for short-term weight
loss.[34] Information on the use of ephedra alkaloids
in sports, however, is scarce. It has been reported
that ephedrine, pseudoephedrine and phenylpropa-
nolamine, as a group, accounted for 31% (35 out of
113) of the positive samples detected among 2066
urine specimens collected from competitors in 17
different sports during the period 1986–91.[35] In the
1972 Olympic Games, a 16-year-old US athlete was
compelled to return his gold medal due to ephedrine
use prior to competition and despite claiming that he
had made use of the drug for treatment of his asthma
as prescribed by his physician.[36] More recently, a
Romanian teenage gymnast had her all-around gold
medal taken away at the 2000 Olympic Games in
Sydney, after her doctor gave her a cold remedy
containing pseudoephedrine.[18] Urine concentra-
tions >10 mg/L for ephedrine[37] and >25 mg/L for
pseudoephedrine[38] are considered positive by most
sport governing bodies at present. Besides urinal-
Sports Med 2004; 34 (13)
874
ysis, hair analysis techniques are also being devel-
oped as useful adjuncts to conventional drug testing
for identifying doping cases with ephedrine.[39]
Of interest, in a recent survey, anonymous ques-
tionnaires were distributed to 511 clients entering
five commercial fitness centres in the US.[40] Twen-
ty-five percent of men and 13% of women attend-
ants reported ephedrine use within the previous 3
years; extrapolation from these results (109 subjects
or 21.3%) to a national level would translate into
approximately 2.8 million US recreational athletes
and fitness enthusiasts making use of the drug.[40]
The latest National Collegiate Athletic Association
(NCAA) study of substance use habits of college-
student athletes,[41] involving 21225 individuals
from 713 NCAA member institutions, has also re-
vealed a number of interesting findings. It was
shown that ephedrine use increased from 3.5% in
1997 to 3.9% in 2001 and this was especially true
among female athletes. The frequency of use varied
from 0% (gymnastics, rifle) to 5.5% (lacrosse)
among men, and from 0% (skiing) to 11.8% (ice
hockey) among women.[41] The main reasons stated
for using ephedrine were to improve athletic per-
formance (23.6%), as an appetite suppressant or
weight-loss aid (21.7%), for health reasons in gener-
al (21.5%) and to improve appearance (20.3%).[41]
Also, use of the drug appears now to start for the
majority of student athletes prior to college, i.e. in
high school, contrary to what was observed in 1997,
when ephedrine use began after college.[41]
Several authors have expressed their concern
over ephedrine and pointed out recreational[25] and
adolescent[42] athletes as subsets of the population
especially prone to consuming the drug. Interesting-
ly, however, ephedrine-related alkaloids like pseu-
doephedrine and phenylpropanolamine, but not eph-
edrine itself, are also soon to be legalised in
sports,[18] hence, foretelling an expansion of their
use among professional athletes as well. The combi-
nation of caffeine and ephedra alkaloids may thus
become one of the most popular ergogenic aids
among athletes in the years to come. These two
drugs also coexist in many commercially available
dietary supplements and, in several cases, this is
without being clearly declared on the labels.[43]
Ephedrine and pseudoephedrine share compara-
ble pharmacokinetics, reaching peak plasma con-
 2004 Adis Data Information BV. All rights reserved.
Magkos & Kavouras
centrations approximately 2.4 hours after oral inges-
tion, i.e. slightly later than caffeine.[44] The pharma-
cokinetic disposition of all these compounds in
plasma can be well described by a single-compart-
ment model with a typical rise-then-fall pattern, i.e.
it follows first order, linear kinetics.[44] Half-lives
for elimination from the plasma compartment are
also similar, ranging from 4.5 to 8 hours for ephe-
drine, from 4.5 to 10 hours for pseudoephedrine and
from 3.5 to 8 hours for caffeine.[44] These figures are
in accordance with published values reported for
each compound alone,[29,33,45,46] implying that no
significant pharmacokinetic interaction between the
three drugs takes place when ingested in combina-
tion.[44]
2. Performance Enhancement
2.1 Caffeine
The ergogenic effects of caffeine are well docu-
mented. Since the initial studies by Rivers and Web-
ber,[47] a number of reports have shown that inges-
tion of the drug may enhance exercise performance.
Work by the Costill laboratory[48-50] renewed interest
in caffeine in the late 1970s, wheareas Graham and
Spriet[23] and Spriet[51] in the early 1990s demon-
strated beyond doubt that ingestion of the drug may
result in substantial improvements in endurance.
Almost 20 review articles dealing specifically with
the ergogenicity of caffeine under various exercise
modes have been published during the last 15
years,[12,17,21,25-27,52-63] and their findings will not be
reproduced here. The most consistent observation is
that caffeine can increase time to exhaustion during
submaximal exercise bouts lasting approximately
30–60 minutes. Speed and power output during such
activities may also improve. Aerobic endurance dur-
ing shorter events (5–25 minutes) has been reported
to be either enhanced or unaffected by prior caffeine
ingestion. Positive effects are less frequently ob-
served during shorter-term and more intense bouts,
while the same holds true for incremental exercise.
Finally, the limited data available suggest that caf-
feine may enhance some aspects of the neuromuscu-
lar function in vivo in humans.[63] Although the exact
biochemical mechanisms underlying the ergogenic
effects of caffeine are not fully understood,[12] a
Sports Med 2004; 34 (13)
Caffeine-Ephedrine Mixtures and Exercise
number of cellular actions that could potentially
contribute to or account for these effects have been
identified.[29,64]
2.2 Ephedra Alkaloids
Evidence for a performance-enhancing effect of
ephedrine is equivocal. In fact, and despite being
perceived by the public as an ergogenic agent, most
studies have not demonstrated any kind of improve-
ment in athletic performance following ingestion of
ephedra alkaloids at doses generally considered to
be safe, i.e. up to 120mg.[37,65,66] Foltz et al.[67] were
some of the first to describe the effects of ephedrine-
containing preparations on performance during
high-intensity exercise in four medical students.
Many years later, Sidney and Lefcoe[68] carried out
an elaborate study with 21 healthy males, where the
effects of a low dose of ephedrine (24mg) on several
parameters of exercise capacity were examined.
Ephedrine ingestion did not influence muscle
strength, endurance, power, anaerobic capacity,
speed, reaction time, hand-eye coordination or re-
covery from effort.[68]
Another investigation evaluated the effects of
pseudoephedrine ingestion (120mg), taken approxi-
mately 2 hours prior to testing, on exercise perform-
ance during a 40km cycle ergometry time trial, and
on skeletal muscle function as measured during iso-
metric contractions before and after exercise in ten
male cyclists.[69] For the cycling test, times ranged
from 53.8 to 69.7 minutes after drug ingestion and
from 53.1 to 65.9 minutes after placebo ingestion;
mean times after pseudoephedrine (58.7 ± 1.5 min-
utes) and placebo (58.1 ± 1.4 minutes) were not
significantly different.[69] Likewise, neither maxi-
mum voluntary contraction (MVC) nor time to fa-
tigue were affected by drug ingestion, either before
or after exercise.[69] Corroborating these findings,
Swain et al.[70] studied 20 male cyclists, ten of whom
received typical doses of phenylpropanolamine
(0.33 or 0.66 mg/kg) and the remaining ten were
given pseudoephedrine (1 or 2 mg/kg). There were
no significant improvements in time to exhaustion
during a bicycle ergometry test in either group,
regardless of drug dose.[70]
In a more recent investigation, the effects of
pseudoephedrine (120mg) ingested approximately 2
hours before testing were examined in ten male and
 2004 Adis Data Information BV. All rights reserved.
875
nine female volunteers.[38] The subjects completed a
number of battery tests to evaluate skeletal muscle
function, including MVC measurements, a 60-sec-
ond intermittent isometric handgrip protocol and
dorsi-flexion testing of the right ankle; they also
completed a 30-second maximal cycling test to de-
termine anaerobic power output.[38] No effects of
drug treatment on any of these performance parame-
ters were observed.[38]
Apparently, isolated use of ephedra alkaloids at
recommended doses does not seem to enhance ath-
letic performance under a variety of different exer-
cise modalities. However, in their brief communica-
tion, Walton et al.[71] observed an ergogenic effect in
eleven male athletes, who were given pseu-
doephedrine (120mg) approximately 2 hours prior
to testing, which included measurements of the neu-
romuscular function of the quadriceps muscle
(twitch torque, MVC, post-tetanic torque), submax-
imal cycling ergometry (time to exhaustion at 80%
of maximal oxygen uptake [V̇O2max]), and a series
of two Wingate tests. These investigators reported a
greater (p = 0.04) absolute and relative mean power
output during the Wingate and a strong trend (p <
0.11) towards increased MVC after drug inges-
tion.[71] Another study was undertaken to determine
whether a higher than therapeutic dose of pseu-
doephedrine (180mg) would produce any ergogenic
effects during short-term maximal exercise.[72]
Twenty-two male athletes were recruited and were
given pseudoephedrine or placebo 45 minutes prior
to testing, which included isometric knee extension,
muscle motor unit activation measurements, bench
press at 70% and 100% of one repetition maximum
(1RM), and a 30-second ‘all-out’ cycle test.[72]
Pseudoephedrine increased peak torque by 8.6%
over placebo during knee extension (321.1 ± 62.0 vs
295.7 ± 72.4Nm, respectively), but did not affect
muscle activation; the drug did not influence
weight-lifting performance at either 70% or 100% of
1RM and did not affect total work production during
the 30-second cycle ride; however, it did increase
peak power by 2.8% during the latter test (1262.5 ±
48.5 vs 1228.4 ± 47.1W, respectively).[72]
These findings and those from previous studies
could imply that a threshold dosage level may exist
for the ergogenic effects of ephedra to manifest.
Alternatively, the drug may be effective in increas-
Sports Med 2004; 34 (13)
876
a b
35
* *
30
Time to exhaustion (min)
25
* weight basis; hence, for instance, a 120mg dose of
20
15
10
5
0
PL CAF EPH C+E PL CLE LCE LCLE
Fig. 1. Effects of caffeine (CAF) and ephedrine (EPH) alone or in
combination (C+E) on time to exhaustion during submaximal exer-
cise. (a) Eight recreationally active male subjects ingested placebo
(PL), CAF 5 mg/kg, EPH 1 mg/kg or C+E (CAF 5 mg/kg and EPH 1
mg/kg). After 90 minutes of rest they performed a 5-minute warm-
up at 50% of V̇O2peak and then cycled to exhaustion at 85% of
V̇O2peak. * p < 0.05 for C+E vs CAF and PL. (b) Twelve untrained
male subjects ingested PL, caffeine plus low ephedrine (CLE) [CAF
5 mg/kg and EPH 0.8 mg/kg], low caffeine plus ephedrine (LCE)
[CAF 4 mg/kg and EPH 1 mg/kg] or low caffeine plus low ephedrine
(LCLE) [CAF 4 mg/kg and EPH 0.8 mg/kg]. After 90–120 minutes of
rest, they cycled to exhaustion as described above. * p < 0.05 for all
drug combination treatments vs PL. Values are shown as mean ±
standard error.[74,75] V̇O2peak = peak oxygen consumption.
ing performance only during specific types of activi-
ty and only under certain circumstances. The first
possibility, however, is not supported by more re-
cent data. Chester et al.[73] had eight male runners
perform an exercise session consisting of 20 minutes
of submaximal running at 70% of V̇O2max, followed
by a 5km time trial on the treadmill, under
pseudoephedrine (60mg four times daily, i.e. 240
mg/day), phenylpropanolamine (25mg four times
daily, i.e. 100 mg/day) or placebo conditions; treat-
ments were administered over the 36-hour period
prior to testing.[73] There were no differences in time
to complete the runs between any of these trials.[73]
2.3 Caffeine-Ephedrine Mixtures
As exemplified in sections 2.1 and 2.2, although
caffeine alone can be ergogenic under many circum-
stances, ephedra alkaloids by themselves are proba-
bly not. The recent surge of interest has been fuelled
by several contemporary reports indicating that
combined use of caffeine and ephedrine may be of
greater ergogenic benefit than each compound
alone.[25,63] This combination seems timelier now
than ever before, since the use of caffeine and ephe-
 2004 Adis Data Information BV. All rights reserved.
Magkos & Kavouras
drine-related alkaloids, but not ephedrine itself, is
*
about to become unrestricted in sports.[18] It should
be noted here that pseudoephedrine is approximate-
ly 2.5-fold less potent than ephedrine on an equal
the former is equivalent to a 48mg dose of the
latter.[69] Alternatively, ephedrine doses equal to
0.8–1.0 mg/kg (as those used in the studies de-
scribed later in this section) are equivalent to
pseudoephedrine doses of 2–2.5 mg/kg.
In the first of the studies examining the effects of
caffeine-ephedrine mixtures on athletic perform-
ance, ingestion of a combined dose of caffeine (5
mg/kg) plus ephedrine (1 mg/kg) resulted in an
approximate 38% improvement in time to exhaus-
tion compared with placebo during submaximal cy-
cle ergometry exercise (figure 1a).[74] This effect
was greater than that of caffeine or ephedrine alone,
the latter two being not significantly different from
placebo,[74] and was also preserved with lower drug
doses that minimised adverse effects (figure 1b).[75]
The same investigators undertook two field trials
where they also demonstrated an ergogenic effect of
the combination treatment. In the first study, nine
male recreational runners performed the Canadian
Forces Warrior Test, which consists of 3.2km of
PL
CAF
EPH
C+E
14.5 *
14 * * *
Pace (km/h)
13.5
13
12.5
12
11.5
0 1 2 3 4 5 6 7 8 9 10
Distance (km)
Fig. 2. Effects of caffeine (CAF) and ephedrine (EPH) alone or in
combination (C+E) on running pace during a 10km time trial.
Twelve recreational runners (ten males and two females) ingested
placebo (PL), CAF 4 mg/kg, EPH 0.8 mg/kg or C+E (CAF 4 mg/kg
and EPH 0.8 mg/kg). After 90 minutes of rest they performed a
10km run while wearing a helmet and backpack weighing 11kg; the
intensity of this effort was >90% of V̇O2peak. Values are shown as
mean ± standard error. * p < 0.05 for EPH and C+E vs CAF and PL
(reproduced from Bell et al.[77] with permission). V̇O2peak = peak
oxygen consumption.
Sports Med 2004; 34 (13)
Caffeine-Ephedrine Mixtures and Exercise
1200
* *
1000
* *
Power output (W)
800
600
400
200
0
5 10
Fig. 3. Effects of caffeine (CAF) and ephedrine (EPH) alone or in combination (C+E) on anaerobic exercise performance during the Wingate
test. Sixteen male volunteers ingested placebo (PL), CAF 5 mg/kg, EPH 1 mg/kg or C+E (CAF 5 mg/kg and EPH 1 mg/kg). After 90 minutes
of rest they performed the 30-second Wingate cycle test. Values for power output are shown as mean ± standard error. * p < 0.05 for EPH
and C+E vs CAF and PL.[78]
running while wearing ‘fighting order’ weighing
approximately 11kg.[76] The trials were performed in
sets of two runs, i.e. two tests were done 24 hours
apart, with placebo or caffeine (375mg) plus ephe-
drine (75mg) being ingested alternatively during the
first or the second day. Run times were significantly
reduced by approximately 4.5% when caffeine and
ephedrine were ingested 2 hours prior to exercise
compared with placebo (14.6–14.8 vs 15.3–15.5
minutes, respectively).[76] In the second study, ten
male and two female recreational runners performed
a 10km race while wearing the same 11kg gear,
approximately 1.5 hours after ingesting placebo,
caffeine (4 mg/kg), ephedrine (0.8 mg/kg) or a com-
bination of the two drugs (4 mg/kg caffeine and 0.8
mg/kg ephedrine).[77] In this case, time to complete
the run for the ephedrine trials (45.5 ± 2.9 and 45.7 ±
3.3 minutes for ephedrine alone and ephedrine-caf-
feine, respectively) was significantly reduced by
approximately 2% compared with the non-ephe-
drine trials (46.0 ± 2.8 and 46.8 ± 3.2 minutes for
caffeine alone and placebo, respectively); this was
attributed to an apparent increase in pace (approxi-
mately +0.5 km/h) over the last 5km of the run
(figure 2).[77]
The combined drug treatment seems to be of
ergogenic benefit not only during submaximal
short- and long-term exercise, but in various other
 2004 Adis Data Information BV. All rights reserved.
877
PL
CAF
EPH
C+E
15 20 25 30
Time (sec)
exercise modalities as well. For instance, Bell et
al.[78] demonstrated a small (1–2%) but significant
increase in power output during the 30-second Win-
gate test following ingestion of ephedrine alone or in
combination with caffeine, compared with caffeine
alone or placebo; this effect was only evident early
during the ride (figure 3). In another experiment,
time to exhaustion and oxygen deficit during a max-
imal accumulated oxygen deficit (MAOD) test were
increased by 7–8% following administration of caf-
feine (alone or with ephedrine) compared with ephe-
drine alone or placebo; however, accumulated oxy-
gen consumption (V̇O2) was not significantly affect-
ed (figure 4).[78] In both instances, therefore,
ingestion of the caffeine-ephedrine mixture was as-
sociated with significant improvements in perform-
ance, regardless of the relative contribution of each
drug to the ergogenic effect of the combined prepa-
ration.
A recent study from the same laboratory[79] (see
also Pasternak et al.[80]) examined the effects of
caffeine and ephedrine, alone or in combination, on
muscular endurance during a weight-lifting circuit
consisting of three supersets, each comprising leg
press followed by bench press. Again, compared
with the non-ephedrine trials (caffeine alone and
placebo), ephedrine ingestion, either alone or with
caffeine, resulted in significant increases in the
Sports Med 2004; 34 (13)
878 Magkos & Kavouras

Oxygen deficit
·
Accumulated VO2
Time to exhaustion

7000 130
*
6000 125
*
120

Time to exhaustion (sec)

5000

* 115
Oxygen (mL)

4000
*
110
3000
105
2000
100

1000 95

0 90
PL CAF EPH C+E PL CAF EPH C+E

Fig. 4. Effects of caffeine (CAF) and ephedrine (EPH) alone or in combination (C+E) on anaerobic exercise performance during the maximal
accumulated oxygen deficit (MAOD) test. Eight male volunteers ingested placebo (PL), CAF 5 mg/kg, EPH 1 mg/kg or C+E (CAF 5 mg/kg
and EPH 1 mg/kg). After 90 minutes of rest they performed the MAOD test, i.e. supramaximal cycling at 125% of V̇O2peak. Values are
shown as mean ± standard error. * p < 0.05 for CAF and C+E vs EPH and PL.[78] V̇O2 = oxygen consumption; V̇O2peak = peak oxygen
consumption.

mean number of repetitions completed during the
first superset for both the leg-press and bench-press
exercises, but no effect was evident for the remain-
ing two supersets (figure 5).[79] Consequently, the
total work produced for the whole circuit pro-
gramme (calculated as the product of the number of
repetitions and the weight lifted during the concen-
tric phase of the exercise) was increased by more
than 20% after ephedrine (9442 ± 3306kg) and
caffeine plus ephedrine (9989 ± 3586kg) ingestion,
than after caffeine (7546 ± 2971kg) or placebo
(8347 ± 2724kg) ingestion.[79]
Collectively, these data lend strong support to the
premise that both aerobic and anaerobic perform-
ance is improved, although to a variable degree,
after ingestion of a combination of caffeine plus
ephedrine. Still, available research is extremely lim-
ited and quite heterogeneous in nature, thus any
conclusions remain tentative. While there seems to
be little doubt that caffeine-ephedrine mixtures can
improve athletic performance relative to placebo,
the putative additional effect of ephedrine, on top of
that caused by caffeine alone (i.e. caffeine-ephe-
drine vs caffeine alone) is less consistent and needs
further investigation. The two drugs act indepen-
dently and probably additively rather than interac-
tively, i.e. there seem to be no synergistic ef-
fects.[74,77,78,81,82] It is of interest to note that groups
of subjects participating in the above-mentioned
experiments consisted of individuals who were reg-
ular coffee drinkers, or had variable habitual caf-
feine consumption and who did not abstain from
caffeine-containing products prior to testing for a
period longer than 24–48 hours.[74-79] Thus, it seems
that caffeine habituation and perhaps the develop-
ment of tolerance to some caffeine-induced physio-
logical effects (e.g. cardiovascular stimulation and
catecholamine release),[83] do not impair the
ergogenic potential of the mixed treatment. This is
in agreement with the results for the ergogenic na-
ture of isolated caffeine use[84] and attests to the
general consensus that caffeine habituation and
withdrawal have no major influence of the perform-
ance-enhancing ability of the drug.[12,63]

 2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (13)
Caffeine-Ephedrine Mixtures and Exercise 879

3. Hormonal Response vestigators observed that caffeine alone enhanced

Studies examining the hormonal response to the
ingestion of caffeine, ephedrine or their combination
have generally been limited to catecholamines (epi-
nephrine and norepinephrine) and monoamines
(dopamine). In most circumstances, epinephrine
levels were increased throughout exercise in the
caffeine trials (alone or with ephedrine) compared
with ephedrine alone or placebo.[74,78] It seems that
caffeine-induced increases in plasma epinephrine
are independent of the type of exercise, since they
have been observed during either submaximal
steady-state bouts[74] or anaerobic bouts such as the
Wingate and the MAOD tests.[78] In both instances,
however, the drugs led to higher epinephrine con-
centrations already before exercise initiation, i.e.
after the initial period of rest following drug inges-
tion.[74,78] Apparently, therefore, individuals under
the caffeine and caffeine-ephedrine treatments com-
menced exercise with higher epinephrine levels, so
it is not clear whether a catecholaminergic effect
was manifested also during exercise or merely re-
flected a residual effect of the drugs at rest. A very
interesting response was reported by Bell et al.[77] in
their study involving 10km of running at above 90%
of peak oxygen consumption (V̇O2peak). These in-
a b
25
* EPH
20
*
No. of repetitions
epinephrine concentrations, whereas ephedrine
alone attenuated this response; as a result, the com-
bined ingestion of both drugs had no effect on the
time course of plasma epinephrine, which was strik-
ingly similar to that after placebo ingestion (figure
6).[77]
The results for norepinephrine are quite mixed.
During submaximal steady-state exercise lasting ap-
proximately 15 minutes, norepinephrine levels were
unaffected by caffeine, ephedrine or their combina-
tion; still, they were higher at exhaustion in the two
ephedrine trials.[74] On the other hand, during the
first 30 minutes of a 10km run, norepinephrine
concentrations were greater for the caffeine and the
caffeine-ephedrine treatments compared with ephe-
drine alone and placebo.[77] Moreover, during the
Wingate cycle ride, norepinephrine was similarly
increased by both caffeine and ephedrine, and their
combination was additive (i.e. caffeine-ephedrine >
caffeine alone = ephedrine alone > placebo).[78] No
effect of either drug or their combination, however,
was evident during the MAOD cycle test.[78] Wheth-
er the variability in norepinephrine responses could
rest on the different exercise modalities or on other
factors is unknown at present. Overall, ingestion of
caffeine and ephedrine combined seems to be able to
PL
CAF
C+E

*
15 *

10

0
Set 1 Set 2 Set 3 Set 1 Set 2 Set 3

Fig. 5. Effects of caffeine (CAF) and ephedrine (EPH) alone or in combination (C+E) on weight-lifting performance. Thirteen males ingested
placebo (PL), CAF 4 mg/kg, EPH 0.8 mg/kg or C+E (CAF 4 mg/kg and EPH 0.8 mg/kg). After 90 minutes of rest, they performed a weight-
training circuit consisting of three supersets, each comprising leg press (at 80% of 1RM to exhaustion) followed by bench press (at 70% of
1RM to exhaustion) with 2 minutes of rest in between. Values for the number of repetitions during leg press (a) and bench press (b) are
shown as mean ± standard error. * p < 0.05 for EPH and C+E vs CAF and PL.[79] 1RM = 1 repetition maximum.

 2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (13)
880 Magkos & Kavouras

PL
CAF
EPH
5 C+E

4 *
Epinephrine (nmol/L)

* †§
3

* ‡§
2 * ‡§

0
0 5 10 15 20 25 30 35 40 45 50

Time (min)
Fig. 6. Effects of caffeine (CAF) and ephedrine (EPH) alone or in combination (C+E) on epinephrine levels during exercise. 12 recreational
runners (10 males and 2 females; 6 regular coffee drinkers and 6 irregular or non-caffeine users) ingested placebo (PL), CAF 4 mg/kg, EPH
0.8 mg/kg or C+E (CAF 4 mg/kg and EPH 0.8 mg/kg). After 90 minutes of rest they performed a 10km run while wearing a helmet and
backpack weighing 11kg; the intensity of this effort was >90% of V̇O2peak. Values are shown as mean ± standard error (reproduced form
Bell et al.,[77] with permission). V̇O2peak = peak oxygen consumption; * p < 0.05 vs PL; † p < 0.05 vs EPH; ‡ p < 0.05 vs CAF; § p < 0.05 vs
C+E.

produce sporadic increases in plasma nore-
pinephrine, at least during some exercise types. In
contrast, much more consistent findings have been
reported for dopamine: ingestion of ephedrine alone
or ephedrine plus caffeine has uniformly resulted in
markedly increased dopamine concentrations com-
pared with caffeine alone or placebo treatments; this
was regardless of the type of exercise, i.e. aerobic or
anaerobic and submaximal or maximal (figure
7).[74,77,78]
Considering the potential contribution of each
individual drug to these effects, acute administration
of caffeine has been associated with higher epineph-
rine concentrations at rest and during exercise of
various modalities and only rarely has this not been
observed (for review see Magkos and Kavouras[63]).
On the contrary, caffeine-induced increases in nore-
pinephrine levels are seldom observed.[63] A recent
investigation by Graham et al.,[85] however, found
that muscle norepinephrine spillover during exercise
more than doubled after caffeine ingestion com-
pared with placebo. With respect to dopamine, the
limited available studies indicate no effects of caf-
feine either at rest[83,86,87] or during exercise,[87] al-
though one study reported an increase in dopamine
levels after caffeine ingestion during the recovery
period from exercise.[87] Unfortunately, studies ex-
amining the isolated use of ephedra alkaloids during
exercise in humans have not measured hormonal
concentrations.
In summary, it seems that ingestion of caffeine-
ephedrine mixtures leads to increased epinephrine
concentrations at rest and during exercise, and this is
probably due to the caffeine content of the prepara-
tion. Significant increases in dopamine levels during
exercise are also observed, but by contrast, these
seem to result from the ephedrine component of the
mixture. Norepinephrine responses are quite varia-
ble. Both drugs may enhance norepinephrine turno-
ver, but each one alone only modestly; a combina-
tion of the two, however, probably potentiates this
effect.
4. Substrate Metabolism
Unfortunately, very limited information is availa-
ble with respect to substrate shifts during exercise
following ingestion of caffeine-ephedrine mixtures.
The most well characterised metabolite response is
probably that of lactate. Plasma lactate concentra-
tions have been reported to increase after ingestion

 2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (13)
Caffeine-Ephedrine Mixtures and Exercise 881

of caffeine plus ephedrine; this is a rather uniform
finding, as it has been observed during a steady-state
submaximal run lasting approximately 15 min-
utes,[74] an aerobic 10km time trial lasting approxi-
mately 45 minutes[77] and an anaerobic 30-second
Wingate cycle test.[78] It seems that the two drugs
have additive effects and both account for the in-
crease in lactate levels, although caffeine may con-
tribute to a greater extent.[74,77,78] In accordance with
this hypothesis, Graham[12] recently outlined that
caffeine ingestion alone has very often been ob-
served to increase blood lactate during exercise. On
the contrary, isolated use of ephedra alkaloids has
consistently not induced any change in lactate con-
centrations during various exercise modes, such as
prolonged aerobic cycling,[69] submaximal steady-
state running,[73] ‘all-out’ anaerobic cycling[38,72] or
isometric handgrip exercise.[38] There is only one
report of a tendency (p < 0.15) for pseudoephedrine
Steady-state cycling
* *
2 1.6
Dopamine (nmol/L)
to increase blood lactate levels at the end of the
Wingate test,[71] a finding that is not supported by
others.[38,72]
A similar pattern of response as that for lactate
has also been observed in the case of blood glucose.
Ingestion of caffeine-ephedrine mixtures has been
associated with higher concentrations of glucose
during various exercise modes compared with in-
gestion of either compound alone or placebo.[74,77,78]
In this case, the two drugs seem to contribute equal-
ly to the hyperglycaemic effect observed after their
combined use.[74,77,78] Still, although caffeine alone
may sometimes lead to increased blood glucose
levels compared with placebo, generally it exerts no
such effect.[12] Likewise, the only study that mea-
sured glucose concentrations during exercise after
pseudoephedrine, phenylpropanolamine or placebo
ingestion found no significant differences between
the treatments.[73] Therefore, a synergistic effect
Wingate test PL
CAF
EPH
C+E

1.5 1.2
*
1 § 0.8

0.5 0.4

0 0

Long-distance running MAOD test

*
6 1.2
* *
Dopamine (nmol/L)

5
0.9
4
3 0.6
2
0.3
1
0 0
0 15 30 End Pre-exercise Post-exercise
Time (min)

Fig. 7. Effects of caffeine (CAF) and ephedrine (EPH) alone or in combination (C+E) on dopamine levels during various exercise types.
Steady-state cycling: see figure 1 for details on the experimental protocol. § p < 0.05 for C+E vs CAF and placebo (PL); * p < 0.05 for EPH
and C+E vs CAF and PL.[74] Long-distance running: see figure 2 for details on the experimental protocol. * p < 0.05 for EPH and C+E vs CAF
and PL (reproduced from Bell et al.,[77] with permission). Wingate test: see figure 3 for details on the experimental protocol. * p < 0.05 for
EPH and C+E vs CAF and PL.[78] MAOD test: see figure 4 for details on the experimental protocol. * p < 0.05 for EPH and C+E vs CAF and
PL.[78] All values are shown as mean ± standard error. MAOD = maximal accumulated oxygen deficit.

 2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (13)
882
cannot be ruled out in the case of blood glucose
when caffeine and ephedrine are ingested in combi-
nation.
With respect to free fatty acid (FFA) and glycerol
concentrations, the limited information available
suggests that no significant alteration occurs after
ingesting a mixture of caffeine plus ephedrine, be-
yond that caused by exercise itself or by each drug
separately.[74,77] During steady-state running at 85%
of V̇O2peak, FFA concentrations were similar be-
tween placebo, ephedrine and caffeine plus ephe-
drine trials, but in all three treatments, FFA levels
were approximately 100–150 µmol/L lower than in
the caffeine-only trial, both prior to and during
exercise.[74] On the contrary, during a time trial
involving running as fast as possible (at above 90%
of V̇O2peak), FFA levels were similar for all condi-
tions at the beginning of exercise, but were sporadi-
cally increased in the ephedrine-containing trials
(ephedrine and caffeine-ephedrine) compared with
the non-ephedrine ones (caffeine and placebo).[77]
Similarly, plasma glycerol has been reported ei-
ther to increase[74] or remain unchanged[77] after
consumption of caffeine plus ephedrine. In both
instances, however, ingestion of caffeine alone led
to significantly higher glycerol concentrations than
ephedrine alone or placebo.[74,77] Although these
findings are difficult to interpret, it is probably caf-
feine that brings about any changes in circulating
lipid fuels observed following ingestion of caffeine-
ephedrine mixtures. Isolated use of caffeine has
been associated with increased FFA concentrations,
yet this has been observed much more frequently at
rest than during exercise; the effects of the drug on
glycerol levels are less clear, with both increases and
no changes being reported (reviewed in Magkos and
Kavouras[63]). On the other hand, it is disappointing
to note the almost complete lack of studies measur-
ing FFA and/or glycerol concentrations during exer-
cise following ingestion of ephedra alkaloids alone;
however, in those who did, no significant effects
were reported.[73]
5. Cardiovascular Effects
Ingestion of preparations containing caffeine and
ephedrine approximately 1.5–2 hours before com-
mencing exercise has repeatedly been shown to re-
sult in an increase in heart rate (HR) above that
 2004 Adis Data Information BV. All rights reserved.
Magkos & Kavouras
caused by exercise alone and this has been observed
during either steady-state submaximal exercise last-
ing 10–30 minutes,[74,75] or during short-distance[76]
and long-distance[77] time trials. A similar but tran-
sient increase in HR has also been observed during
submaximal (50% of V̇O2peak) exercise in a hot
(40°C) and humid (30% relative humidity) environ-
ment, following ingestion of the two drugs.[88] A
question remains, however, as to whether this re-
sponse is due to caffeine, ephedrine or both. During
running at 85% of V̇O2peak, the combination of
caffeine with ephedrine and to a lesser extent, caf-
feine alone, significantly increased HR above that
recorded in the other two trials (ephedrine alone and
placebo).[74] When running at >90% of V̇O2peak,
however, treatment with ephedrine (alone or with
caffeine) produced a slight but significant increase
in the mean HR response throughout exercise (176 ±
12 beats/min) compared with the non-ephedrine tri-
als (caffeine alone and placebo, 174 ± 13 beats/
min).[77]
There are no studies available regarding the ef-
fects of caffeine-ephedrine mixtures on the pressor
response to exercise. Jacobs et al.[79] recently ob-
served an increase in systolic, but not diastolic blood
pressure (BP) just before commencing a weight-
lifting circuit, following ingestion of ephedrine
(alone or with caffeine) compared with caffeine
alone and placebo. However, no data on BP during
exercise were reported. In an earlier communica-
tion, the same group measured BP responses over a
48-hour period involving only activities of daily
living (no specific exercise), under placebo, caffeine
(375mg), ephedrine (75mg) or a combination of the
latter two treatments.[89] They, too, observed that
systolic BP increased the most after the caffeine-
ephedrine treatment, reaching hypertensive values
after 1 hour (138 ± 11mm Hg); each drug alone also
produced a significant increase in systolic BP (132 ±
10 and 126 ± 10mm Hg after ephedrine and caffeine,
respectively) compared with placebo (118 ± 8mm
Hg).[89] The pattern of response at the 1-hour mark
was caffeine-ephedrine > ephedrine = caffeine >
placebo, but at 8 hours and thereafter, systolic BP
had returned to baseline.[89] The three drug treat-
ments also produced similar and significant in-
creases in diastolic BP, but these were considerably
smaller in magnitude and duration.[89]
Sports Med 2004; 34 (13)
Caffeine-Ephedrine Mixtures and Exercise 883

PL
Studies into the effects of ephedra alkaloids alone Oxygen consumption CAF
on HR and BP prior to or during exercise and EPH
recovery have generally provided mixed results, 4.0 C+E
with either increases or no alterations being ob- 3.5
served.[36,68,70,73,90,91] The results for the isolated use 3.0
of caffeine are more homogeneous, with the majori- 2.5
ty of evidence showing no effect on HR during
2.0
exercise[48,49,85,87,92-102] and an increase in BP,[85,92,99]
although some have also reported an increase in
Carbon dioxide production
HR.[103-105] It seems, therefore, that both drugs are
able to influence HR and/or BP during exercise, 4.0
albeit modestly. Ephedrine, however, probably con- 3.5

(L/min)
tributes to a greater extent to the uniform increases 3.0
in HR observed during submaximal aerobic exercise
2.5
after ingestion of caffeine-ephedrine mixtures.[74-77]
2.0
6. Pulmonary Function and
Gas Exchange Minute ventilation

150
Measurements of pulmonary gas exchange dur-
ing short-term submaximal steady-state exercise in 125

humans, following ingestion of caffeine-ephedrine 100

mixtures, have generally revealed no significant ef-
fects on V̇O2, carbon dioxide release (V̇CO2) or
minute ventilation (V̇E). In one study, all variables
increased progressively during exercise, but there
were no differences between the various drug treat-
ments and placebo; timecourse curves were almost
super-imposable (figure 8).[74] Similar results have
been obtained regardless of whether a high or a low
caffeine-ephedrine dose was administered.[75] How-
ever, during a time trial consisting of 10km of
running, V̇O2, V̇CO2 and V̇E were inconsistently
affected by treatment: ingestion of ephedrine (alone
or with caffeine) only tended to increase V̇O2 and
did increase V̇CO2 after 9km of running, whereas
V̇E was significantly greater for the caffeine-only
trial at 15 minutes into exercise, and for the caffeine-
ephedrine trial at the 9km time point.[77] Also, dur-
ing submaximal exercise at 50% of V̇O2peak in a hot
and humid environment, lasting approximately 2
hours, the combination of caffeine plus ephedrine
has been shown to result in increased V̇O2 and V̇E
relative to placebo/control treatments.[88] ‘Perform-
ance’, however, as reflected by exercise tolerance
times, was similar for the caffeine-ephedrine and the
placebo treatments, and it was greater in both com-
pared with control.[88] Available literature, therefore,
is rather controversial. It may be that caffeine-ephe-
75
50
1 3 5 7 End
Time (min)
Fig. 8. Effects of caffeine (CAF) and ephedrine (EPH) alone or in
combination (C+E) on respiratory gas exchange during exercise.
Eight recreationally active males ingested placebo (PL), CAF 5 mg/
kg, EPH 1 mg/kg or C+E (CAF 5 mg/kg and EPH 1 mg/kg). After 90
minutes of rest they performed a 5-minute warm-up at 50% of
V̇O2peak and then cycled to volitional exhaustion at 85% of V̇O2peak.
For presentation reasons, it was assumed that exhaustion occurred
at the same time for all treatments, denoted as ‘end’ (although it
actually corresponded to different times). Respiratory gas ex-
change variables were measured continuously during exercise us-
ing an automated metabolic cart. Values are shown as mean ±
standard error. No significant differences between any of the treat-
ments and at any time point were observed.[74] V̇O2peak = peak
oxygen consumption.
drine mixtures may enhance pulmonary gas ex-
change, but only during longer-term and/or more
demanding efforts.
Looking into the isolated effects of each drug,
ephedra alkaloids have not been shown to result in
any consistent and/or significant alterations in the
pulmonary function and gas exchange during exer-
cise in humans, irrespective of the type of alkaloid
(ephedrine, pseudoephedrine, phenylpropano-
lamine) and the mode of exercise (steady-state sub-

 2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (13)
884 Magkos & Kavouras

PL
CAF
EPH
10
C+E

6
RPE

*
4 *

0
0 2.5 5 7.5 10 12.5 15 17.5 20
Time (min)
Fig. 9. Effects of caffeine (CAF) and ephedrine (EPH) alone or in combination (C+E) on rating of perceived exertion (RPE) during exercise.
Eight recreationally active male volunteers ingested placebo (PL), CAF 5 mg/kg, EPH 1 mg/kg or C+E (CAF 5 mg/kg and EPH 1 mg/kg).
After 90 minutes of rest they performed a 5-minute warm-up at 50% of V̇O2peak and then cycled to volitional exhaustion at 85% of V̇O2peak.
Subjects were asked to rate their perceived exertion on the Borg scale. Values are shown as mean ± standard error. * p < 0.05 for C+E vs
CAF and PL.[74] V̇O2peak = peak oxygen consumption.

maximal, incremental, time trials).[36,68,70,73,91] Only
one study could be identified where pseu-
doephedrine (180mg) was reported to enhance lung
function, as witnessed by significant post-exercise
increments in the forced vital capacity (FVC), i.e.
the volume expired from maximum inspiration to
rapid forced maximum exhalation, and the forced
expiratory volume in 1 second (FEV1); the forced
expiratory ratio at the first second (FER1), however,
calculated as the ratio of FEV1 to FVC and used as a
measure of airway resistance, was not different.[72]
With respect to the pulmonary gas exchange during
exercise following acute caffeine administration, ev-
idence abounds but is rather heterogeneous in na-
ture: some studies observed an increase in exercise
V̇O2 after caffeine ingestion,[49,92,102,106-109] whereas
others reported no effects on V̇O2, V̇CO2, or
V̇E.[48,84,85,87,97,99,110-113]
7. Psychophysiological Correlates
In addition to putative actions in the periphery,
both caffeine and ephedra alkaloids have considera-
ble stimulatory effects on the CNS.[114-116] Ephe-
drine, pseudoephedrine, phenylpropanolamine and
caffeine act on peripheral and central neurons, and
exert their effects either by binding directly to cell
surface receptors or by increasing release and/or
inhibiting reuptake of neurotransmitters, which are
then available to bind to and activate receptors.[117]
Alteration of brain neurotransmitter function lead-
ing to reduced sensation of effort, for instance, may
be a plausible mechanism by which caffeine-ephe-
drine mixtures could enhance athletic performance.
In fact, the subjective feeling of effort during sub-
maximal steady-state exercise, as measured by the
rating of perceived exertion (RPE), has been shown
to be less after ingestion of caffeine and ephedrine
combined, than after ingestion of each drug alone or
placebo; this coincided with delayed onset of fatigue
under the caffeine-ephedrine treatment (figure 9).[74]
Also, the reduction in RPE does not seem to depend
on the exact dose of caffeine and ephedrine in the
mixture.[75]
It was reported recently that RPE during a time
trial involving 10km of running was similar between
placebo, caffeine, ephedrine, and caffeine plus ephe-
drine treatments, and this was despite the fact that
pace was significantly higher in the ephedrine trials
(alone or with caffeine) compared with the non-
ephedrine trials (caffeine and placebo).[77] From a
simplistic point of view, this means that subjects
under ephedrine were able to run faster, i.e. exercise

 2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (13)
Caffeine-Ephedrine Mixtures and Exercise
at a higher intensity, and yet, perceive this effort as
less intense. Although these findings imply that it is
the ephedrine component that is responsible for the
reduced sensation of effort following ingestion of
caffeine-ephedrine mixtures, studies examining the
isolated effects of ephedra alkaloids have failed to
support this notion.[36,68,70,73,91] On the other hand,
caffeine alone may indeed be able to re-
duce[48,97,101,102,109,118,119] or strongly tend to re-
duce[93,120] RPE during various exercise modalities,
although not uniformly.[87,99,100,113,121]
Of interest are the results reported in the initial
study by Ivy et al.,[49] where nine trained cyclists
ingested placebo or caffeine (250mg before and
250mg during exercise) and then performed 120
minutes of isokinetic cycling at 80 rpm. In this type
of cycle ergometry, speed is fixed and resistance is
variable, thus work production is also variable. It
was shown that RPE was similar between the caf-
feine (12.3 ± 0.34) and the placebo (13.3 ± 0.20)
trials, despite total work produced being significant-
ly greater (+7.4%) under the drug treatment.[49] This
finding was subsequently confirmed by others[96,122]
and is equivalent to that reported by Bell et al.[77] for
caffeine plus ephedrine, referred to earlier in this
section. Recently, caffeine alone was shown to be
effective in decreasing RPE during high-intensity
exercise (80% of V̇O2max: 14.7 ± 2.2 vs 15.6 ± 2.3
for caffeine and placebo, respectively) but not dur-
ing moderate-intensity exercise (50% of V̇O2max:
8.8 ± 1.2 vs 8.6 ± 1.1, for caffeine and placebo,
respectively).[102] This implies that the drug may
become increasingly capable of reducing sensation
of effort as more strenuous activity is being per-
formed. Collectively, it is difficult to weigh the
relative contribution of caffeine and ephedrine in the
reduction of RPE during exercise after ingestion of
caffeine-ephedrine mixtures, but it is clear that such
a CNS-related mechanism is operational in vivo and
could indeed be responsible for the ergogenic effects
of the combined drug treatment.
8. Conclusion
In light of the fact that caffeine and ephedrine-
related compounds such as pseudoephedrine and
phenylpropanolamine are about to legalised in
sports,[18] their use by professional athletes can be
expected to rise considerably in the foreseeable fu-
 2004 Adis Data Information BV. All rights reserved.
885
ture. The decision of sport governing bodies to
remove caffeine and ephedra alkaloids from the list
of banned substances is unexpected, since caffeine
is one of the few ergogenic aids with documented
efficiency,[12,63] but also, its combination with ephe-
drine, as outlined in this article, may be even more
efficacious in increasing athletic performance than
each drug separately. This has been demonstrated in
various different exercise types, including submax-
imal steady-state aerobic exercise, short- and long-
distance running, maximal and supramaximal anaer-
obic cycling, and weight lifting (see section 2.3).
The fact that use of ephedrine per se will still be
restricted is probably of little significance, since, for
instance, pseudoephedrine at 2.5-fold higher doses
is believed to exert similar effects.[69] The above
point notwithstanding, studies into the potential
ergogenicity of mixtures containing caffeine and
ephedra alkaloids like pseudoephedrine and phenyl-
propanolamine have not been conducted to date.
Relevant research in this field, therefore, is clearly
warranted.
Besides performance, caffeine-ephedrine prepa-
rations tend to increase blood lactate and glucose
concentrations during exercise compared with in-
gestion of each drug alone or placebo. Whether this
could reflect an accelerated rate of carbohydrate
metabolism remains unknown at present, but it
seems that the two drugs interact in a way to bring
about these increases. Sporadic enhancements of
FFA and glycerol levels may also be observed, but
these are generally modest in nature. On the other
hand, caffeine-ephedrine mixtures have been shown
to result in marked hormonal responses, such as
increased epinephrine concentrations, probably due
to caffeine, increased dopamine concentrations,
probably due to ephedrine, and perhaps increased
norepinephrine concentrations, probably as a result
of an additive or synergistic effect between the two
drugs. With respect to pulmonary function and gas
exchange during short-term intense exercise, no
physiologically significant effects have been report-
ed. On the other hand, gas exchange may be en-
hanced by caffeine plus ephedrine during longer
and/or more demanding efforts. This possibility is
supported by available studies from the obesity liter-
ature, showing that combination of the two drugs
increases resting metabolic rate.[123-125] A relatively
Sports Med 2004; 34 (13)
886
consistent cardiovascular manifestation is an in-
crease in HR after the combined ingestion of caf-
feine and ephedrine, in addition to that caused by
exercise itself. Finally, evidence to date strongly
suggests that caffeine-ephedrine mixtures are effec-
tive in decreasing the sensation of effort (i.e. RPE)
during various exercise modalities. Although this
may seem to result from the ingestion of caffeine
rather than ephedrine, an additive or synergistic
effect cannot be ruled out, bearing in mind the
multiple CNS-related actions of both drugs.[114-117]
For instance, increased dopamine availability after
ingestion of caffeine plus ephedrine could readily
enhance brain dopaminergic activity, thus sup-
pressing brain 5-hydroxytryptamine synthesis and
metabolism; theoretically, this could reduce the lim-
iting for performance influence of central fa-
tigue.[126]
It is evident that scientific knowledge regarding
the physiological, metabolic and performance-en-
hancing effects of caffeine-ephedrine mixtures dur-
ing exercise in humans is quite limited and heteroge-
neous in nature. These aspects of study are still in
their infancy and additional research is needed to
fully understand and characterise them. As use of
caffeine and ephedra alkaloids by athletes is about to
become unrestricted, it is imperative to elucidate
how these drugs work and what potential ergogenic
benefits they confer. However, before engaging in
the use of such preparations, one should also be
aware of the considerable health risks they might
entail.[127-129] Serious cardiovascular and CNS
events, including hypertension, palpitations, tachy-
cardia, chest pain, stroke, cerebral vascular acci-
dents, myocardial infarction, seizures, and other
psychiatric and autonomic symptoms are only a few;
permanent disabilities and even death have been
documented in several cases.[8,34,130-134] Still, athletes
have a great perseverance and a very long history of
using compounds and techniques potentially je-
opardising their health, and most often, the per-
ceived ergogenic benefits overshadow the docu-
mented adverse effects. It is the authors’ opinion
that this will also be the case for caffeine-ephedra
mixtures.
 2004 Adis Data Information BV. All rights reserved.
Magkos & Kavouras
Acknowledgements
No sources of funding were used to assist in the prepara-
tion of this manuscript. The authors have no conflicts of
interest that are directly relevant to the content of this article.
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Correspondence and offprints: Dr Stavros A. Kavouras, Lab-
oratory of Nutrition and Clinical Dietetics, Department of
Nutrition and Dietetics, Harokopio University, 70 El.
Venizelou Avenue, 176 71 Athens, Greece.
E-mail: skav@hua.gr
Sports Med 2004; 34 (13)