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

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 Preparations containing caffeine and ephedrine have become increasingly Abstract 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 modalities, while ephedrine and related alkaloids have not been shown, as yet, to result in any significant performance improvements. Caffeine-ephedrine mixtures, however, 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, shortand 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 demanding 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 competiadverse health effects[8] and their use is tightly regulated or even completely banned from sports.[9] One tive edge to improve performance and win.[1] Dietaexception is caffeine, and more recently, the combiry manipulations remain one viable alternative for nation of caffeine with ephedra alkaloids.[10] The achieving this goal, especially among elite athletes purpose of this article is to provide an overview of who share a favourable genetic endowment and train the acute effects of combined caffeine plus epheat the limit of what can be considered sustainable.[2] drine ingestion on several parameters of athletic Such attempts are clearly evident in the anecdotal performance and also to discuss some of the metafad diets of ancient Greek athletes,[3] as well as in the bolic and physiological effects of such drug preparacontemporary dietary practices during training and tions during exercise in humans. competition for virtually any kind of sport.[4] Along this line, the field of ergogenic aids has expanded 1. Use in Sports and Legislation1 tremendously in recent years and numerous such compounds, including potential energy sources, me1.1 Caffeine tabolites, recovery aids and drugs, are currently available alone or in combination and promise enCaffeine consumption depends on many factors, hanced endurance, power, strength and speed.[5-7] such as natural source, age, sex, nutritional status, Among the various ergogenic aids, only a few fitness level, peer behaviour and habituation.[11] Use have scientifically documented efficacy; rather, of caffeine in sports is mainly driven by its permost are used by athletes on the basis of personal ceived ergogenic efficiency, but caffeine is also testimonies of unknown truthfulness and anecdotal inexpensive, has little or no acute adverse effects on reports of questionable validity.[5-7] In addition, health, and is a socially acceptable drug.[12] Approxsome formulations may carry significant risks of 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 873 and US adolescent athletes[14] have been reported to greater the benefit. It would not be surprising, theremake use of caffeine for the specific purpose of fore, if some individuals resort to consuming much improving performance. Furthermore, 68% and larger amounts of caffeine than the recommended 64% of >2000 US college-student athletes surveyed ‘optimum’ dose, which lies between 3 and 6 mg/ in 1985 and 1989, respectively, consumed the drug kg.[12,27] Nevertheless, plasma caffeine concentrabut claimed to do so for social reasons only.[15] In tions rise in a dose-dependent manner at rest and competitive sports, there is only one described inciduring exercise, and an oral dose of 9 mg/kg results dence of the use of caffeine suppositories by the US in peak plasma levels of approximately 70–80 μmol/ Cycling Team in the 1984 Olympic Games,[16] while L.[28] This is just below 100 μmol/L, which is condisqualification cases due to caffeine abuse are exsidered the upper limit above which caffeine’s metremely scarce.[17] For instance, in two recent doping tabolism saturates (although saturation may occur at cases, a US sprinter was stripped of a bronze medal even lower concentrations)[29] and is approximately in the 60m at the 1999 World Indoor Championships 2.5-fold lower than the toxic range in humans (i.e. after a positive caffeine test and a female runner 200 μmol/L).[30] Unrestricted use of caffeine by from Suriname lost her gold medal in the 800m at athletes may result in consumption of multi-fold the 2003 Pan American Games over the same ofhigher doses, and one cannot rule out the possibility fence.[18] It is believed, however, that use of stimuof manifestation of serious acute adverse health lants in general[19] and caffeine in particular[20,21] effects, especially among caffeine-naive individuamong both professional and amateur athletes is als. much more widespread. 1.2 Ephedrine Until recently, caffeine was a restricted compound in sports, with a 12 mg/L urinary concentraEphedrine and related compounds (pseution limit set by the International Olympic Commitdoephedrine and phenylpropanolamine) are structee (IOC).[18,22] However, oral doses up to 9 mg/kg turally similar to amphetamines; they are widely ingested approximately 1 hour prior to exercise reused alone, or in combination with caffeine, as sult in postexercise urine levels that are generally weight loss adjuncts or ‘fat burners’ among both below the IOC’s cut-off point,[23,24] while the likeliathletes and non-athletes.[31-33] A recent meta-analyhood to exceed 12 mg/L increases significantly with sis of published studies concluded that such preparahigher caffeine doses, e.g. 13 mg/kg.[24] Fear that the tions may indeed be effective for short-term weight IOC limit in urine might be violated has probably loss.[34] Information on the use of ephedra alkaloids kept consumption of caffeine by athletes at generalin sports, however, is scarce. It has been reported ly low and safe amounts. Amazingly, however, the that ephedrine, pseudoephedrine and phenylpropadrug is about to be taken off the proposed new nolamine, as a group, accounted for 31% (35 out of global list of banned substances, to be drawn up by 113) of the positive samples detected among 2066 the World Anti-Doping Agency.[18] The usefulness urine specimens collected from competitors in 17 of the IOC cut-off has been questioned several times different sports during the period 1986–91.[35] In the in the past[21,25] and caffeine use by athletes has 1972 Olympic Games, a 16-year-old US athlete was repeatedly given rise to significant ethical concompelled to return his gold medal due to ephedrine cerns.[21,25,26] The decision of sport governing bodies use prior to competition and despite claiming that he to legalise caffeine, however, is a diametrically ophad made use of the drug for treatment of his asthma posite response to the concerns of the scientific as prescribed by his physician.[36] More recently, a community and seems hardly logical. In light of this Romanian teenage gymnast had her all-around gold development, use of caffeine among sportspersons medal taken away at the 2000 Olympic Games in can be expected to rise considerably in the foreseeSydney, after her doctor gave her a cold remedy able future. containing pseudoephedrine.[18] Urine concentraIt is also important to note that many athletes tions >10 mg/L for ephedrine[37] and >25 mg/L for perceive the ergogenic effects of a given substance pseudoephedrine[38] are considered positive by most in a ‘linear’ fashion, i.e. the greater the dose the sport governing bodies at present. Besides urinal 2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (13) 874 Magkos & Kavouras ysis, hair analysis techniques are also being develcentrations approximately 2.4 hours after oral ingesoped as useful adjuncts to conventional drug testing tion, i.e. slightly later than caffeine.[44] The pharmafor identifying doping cases with ephedrine.[39] cokinetic disposition of all these compounds in plasma can be well described by a single-compartOf interest, in a recent survey, anonymous quesment model with a typical rise-then-fall pattern, i.e. tionnaires were distributed to 511 clients entering it follows first order, linear kinetics.[44] Half-lives five commercial fitness centres in the US.[40] Twenfor elimination from the plasma compartment are ty-five percent of men and 13% of women attendalso similar, ranging from 4.5 to 8 hours for epheants reported ephedrine use within the previous 3 drine, from 4.5 to 10 hours for pseudoephedrine and years; extrapolation from these results (109 subjects from 3.5 to 8 hours for caffeine.[44] These figures are or 21.3%) to a national level would translate into in accordance with published values reported for approximately 2.8 million US recreational athletes each compound alone,[29,33,45,46] implying that no and fitness enthusiasts making use of the drug.[40] significant pharmacokinetic interaction between the The latest National Collegiate Athletic Association three drugs takes place when ingested in combina(NCAA) study of substance use habits of collegetion.[44] student athletes,[41] involving 21225 individuals from 713 NCAA member institutions, has also re2. Performance Enhancement 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 2.1 Caffeine among female athletes. The frequency of use varied from 0% (gymnastics, rifle) to 5.5% (lacrosse) The ergogenic effects of caffeine are well docuamong men, and from 0% (skiing) to 11.8% (ice mented. Since the initial studies by Rivers and Webhockey) among women.[41] The main reasons stated ber,[47] a number of reports have shown that ingesfor using ephedrine were to improve athletic pertion of the drug may enhance exercise performance. formance (23.6%), as an appetite suppressant or Work by the Costill laboratory[48-50] renewed interest weight-loss aid (21.7%), for health reasons in generin caffeine in the late 1970s, wheareas Graham and al (21.5%) and to improve appearance (20.3%).[41] Spriet[23] and Spriet[51] in the early 1990s demonAlso, use of the drug appears now to start for the strated beyond doubt that ingestion of the drug may majority of student athletes prior to college, i.e. in result in substantial improvements in endurance. high school, contrary to what was observed in 1997, Almost 20 review articles dealing specifically with when ephedrine use began after college.[41] the ergogenicity of caffeine under various exercise Several authors have expressed their concern modes have been published during the last 15 over ephedrine and pointed out recreational[25] and years,[12,17,21,25-27,52-63] and their findings will not be adolescent[42] athletes as subsets of the population reproduced here. The most consistent observation is especially prone to consuming the drug. Interestingthat caffeine can increase time to exhaustion during ly, however, ephedrine-related alkaloids like pseusubmaximal exercise bouts lasting approximately doephedrine and phenylpropanolamine, but not eph30–60 minutes. Speed and power output during such edrine itself, are also soon to be legalised in activities may also improve. Aerobic endurance dursports,[18] hence, foretelling an expansion of their ing shorter events (5–25 minutes) has been reported use among professional athletes as well. The combito be either enhanced or unaffected by prior caffeine nation of caffeine and ephedra alkaloids may thus ingestion. Positive effects are less frequently obbecome one of the most popular ergogenic aids served during shorter-term and more intense bouts, among athletes in the years to come. These two while the same holds true for incremental exercise. drugs also coexist in many commercially available Finally, the limited data available suggest that cafdietary supplements and, in several cases, this is feine may enhance some aspects of the neuromuscuwithout being clearly declared on the labels.[43] lar function in vivo in humans.[63] Although the exact Ephedrine and pseudoephedrine share comparabiochemical mechanisms underlying the ergogenic ble pharmacokinetics, reaching peak plasma coneffects of caffeine are not fully understood,[12] a  2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (13) Caffeine-Ephedrine Mixtures and Exercise 875 number of cellular actions that could potentially nine female volunteers.[38] The subjects completed a contribute to or account for these effects have been number of battery tests to evaluate skeletal muscle identified.[29,64] function, including MVC measurements, a 60-second intermittent isometric handgrip protocol and 2.2 Ephedra Alkaloids dorsi-flexion testing of the right ankle; they also completed a 30-second maximal cycling test to deEvidence for a performance-enhancing effect of termine anaerobic power output.[38] No effects of ephedrine is equivocal. In fact, and despite being drug treatment on any of these performance parameperceived by the public as an ergogenic agent, most ters were observed.[38] studies have not demonstrated any kind of improveApparently, isolated use of ephedra alkaloids at ment in athletic performance following ingestion of recommended doses does not seem to enhance athephedra alkaloids at doses generally considered to letic performance under a variety of different exerbe safe, i.e. up to 120mg.[37,65,66] Foltz et al.[67] were cise modalities. However, in their brief communicasome of the first to describe the effects of ephedrinetion, Walton et al.[71] observed an ergogenic effect in containing preparations on performance during eleven male athletes, who were given pseuhigh-intensity exercise in four medical students. doephedrine (120mg) approximately 2 hours prior Many years later, Sidney and Lefcoe[68] carried out to testing, which included measurements of the neuan elaborate study with 21 healthy males, where the romuscular function of the quadriceps muscle effects of a low dose of ephedrine (24mg) on several (twitch torque, MVC, post-tetanic torque), submaxparameters of exercise capacity were examined. imal cycling ergometry (time to exhaustion at 80% Ephedrine ingestion did not influence muscle of maximal oxygen uptake [V̇O2max]), and a series strength, endurance, power, anaerobic capacity, of two Wingate tests. These investigators reported a speed, reaction time, hand-eye coordination or regreater (p = 0.04) absolute and relative mean power covery from effort.[68] output during the Wingate and a strong trend (p < Another investigation evaluated the effects of 0.11) towards increased MVC after drug ingespseudoephedrine ingestion (120mg), taken approxition.[71] Another study was undertaken to determine mately 2 hours prior to testing, on exercise performwhether a higher than therapeutic dose of pseuance during a 40km cycle ergometry time trial, and doephedrine (180mg) would produce any ergogenic on skeletal muscle function as measured during isoeffects during short-term maximal exercise.[72] metric contractions before and after exercise in ten Twenty-two male athletes were recruited and were male cyclists.[69] For the cycling test, times ranged given pseudoephedrine or placebo 45 minutes prior from 53.8 to 69.7 minutes after drug ingestion and to testing, which included isometric knee extension, from 53.1 to 65.9 minutes after placebo ingestion; muscle motor unit activation measurements, bench mean times after pseudoephedrine (58.7 ± 1.5 minpress at 70% and 100% of one repetition maximum utes) and placebo (58.1 ± 1.4 minutes) were not (1RM), and a 30-second ‘all-out’ cycle test.[72] significantly different.[69] Likewise, neither maxiPseudoephedrine increased peak torque by 8.6% mum voluntary contraction (MVC) nor time to faover placebo during knee extension (321.1 ± 62.0 vs tigue were affected by drug ingestion, either before 295.7 ± 72.4Nm, respectively), but did not affect or after exercise.[69] Corroborating these findings, muscle activation; the drug did not influence Swain et al.[70] studied 20 male cyclists, ten of whom weight-lifting performance at either 70% or 100% of received typical doses of phenylpropanolamine 1RM and did not affect total work production during (0.33 or 0.66 mg/kg) and the remaining ten were the 30-second cycle ride; however, it did increase given pseudoephedrine (1 or 2 mg/kg). There were peak power by 2.8% during the latter test (1262.5 ± no significant improvements in time to exhaustion 48.5 vs 1228.4 ± 47.1W, respectively).[72] during a bicycle ergometry test in either group, regardless of drug dose.[70] These findings and those from previous studies In a more recent investigation, the effects of could imply that a threshold dosage level may exist pseudoephedrine (120mg) ingested approximately 2 for the ergogenic effects of ephedra to manifest. hours before testing were examined in ten male and Alternatively, the drug may be effective in increas 2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (13) 876 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 approximately 2.5-fold less potent than ephedrine on an equal weight basis; hence, for instance, a 120mg dose of 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 described 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 performance, ingestion of a combined dose of caffeine (5 mg/kg) plus ephedrine (1 mg/kg) resulted in an approximate 38% improvement in time to exhaustion compared with placebo during submaximal cycle 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 0 5 10 15 20 25 30 35 a b PL CAF EPH C+E PL CLE LCE LCLE T im e to e xh au st io n (m in )