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Effect of caffeine on metabolism, exercise endurance,and catecholamine responses after withdrawal M. H. VAN SOEREN1 AND T. E. GRAHAM21School of Nursing, Faculty of Health Sciences, University of Western Ontario, London,Ontario N6A 5C1; and 2Human Biology and Nutritional Sciences, University of Guelph,Guelph, Ontario, Canada N1G 2W1 Van Soeren, M. H., and T. E. Graham. Effect of caffeine
assumptions that prior caffeine use alters hormonal on metabolism, exercise endurance, and catecholamine re- and metabolic responses to acute caffeine ingestion and sponses after withdrawal. J. Appl. Physiol. 85(4): 1493–1501, that this process is reversible. If epinephrine is a 1998.—In this study the effects of acute caffeine ingestion on critical element in the ergogenic effect after caffeine exercise performance, hormonal (epinephrine, norepineph- consumption, then attenuation of caffeine-induced in- rine, insulin), and metabolic (free fatty acids, glycerol, glu- creases in plasma epinephrine in habitual caffeine cose, lactate, expired gases) parameters during short-termwithdrawal from dietary caffeine were investigated. Recre- consumers may also dampen the performance and ational athletes who were habitual caffeine users (n ϭ 6) metabolic effects of caffeine during exercise.
(maximum oxygen uptake 54.5 Ϯ 3.3 ml · kgϪ1 · minϪ1 and In vivo, the major mechanism through which caffeine daily caffeine intake 761.3 Ϯ 11.8 mg/day) were tested under acts is as an adenosine-receptor antagonist (1), and all conditions of no withdrawal and 2-day and 4-day withdrawal tissues with adenosine receptors may be affected by from dietary caffeine. There were seven trials in total with a caffeine exposure. Chronic exposure to caffeine results minimum of 10 days between trials. On the day of the exercise in increases in both available adenosine receptors trial, subjects ingested either dextrose placebo or 6 mg/kg and/or receptor-mediated activity in humans and ani- caffeine in capsule form 1 h before cycle ergometry to exhaus- mals (4, 8). Thus, during periods of short-term with- tion at 80–85% of maximum oxygen uptake. Test substances drawal from dietary caffeine, acute caffeine ingestion were assigned in a random, double-blind manner. A finalplacebo control trial completed the experiment. There was no may result in an enhancement of the caffeine-induced significant difference in any measured parameters among responses, such as increases in plasma epinephrine, days of withdrawal after ingestion of placebo. At exhaustion during exercise. We (32) previously demonstrated that in the 2- and 4-day withdrawal trials, there were significant increased epinephrine responses occur during submaxi- increases in plasma norepinephrine in response to caffeine mal exercise in habitual caffeine users with or without ingestion. Caffeine-induced increases in serum free fatty acute ingestion of caffeine. Others have reported con- acids occurred after 4 days and only at rest. Subjects re- flicting epinephrine responses in subjects whose prior sponded to caffeine with increases in plasma epinephrine caffeine usage was known (2, 18, 30). A single study has (P Ͻ 0.05) at exhaustion and prolonged exercise time in all specifically addressed the issue of habituation to caf- caffeine trials compared with placebo, regardless of with- feine during exercise and found no change in substrate drawal from caffeine. It is concluded that increased endur-ance is unrelated to hormonal or metabolic changes and that utilization after a 48-h withdrawal from caffeine (21).
it is not related to prior caffeine habituation in recreational However, these authors did not measure methylxanthines, catecholamines, or endurance, all of which may be criti-cally altered after withdrawal from dietary caffeine.
norepinephrine; epinephrine; methylxanthines; performance; The present study was designed to test the hypoth- esis that caffeine-induced changes in metabolic andcatecholamine responses and in exercise performanceare less pronounced during periods of chronic caffeine ACUTE INGESTION OF CAFFEINE before exercise has been ingestion, thus influencing the ergogenic response to shown to prolong exercise endurance, increase plasma caffeine ingestion. It is anticipated that this dampening epinephrine and serum free fatty acids (FFAs), and of responses will be reversed after short-term with- spare muscle glycogen (14, 18, 29). Research has been drawal from caffeine. Recreational athletes were tested directed toward establishing a causal relationship be- during exercise to exhaustion under conditions of no tween these parameters on the basis of the hypothesis withdrawal and 2 and 4 days of withdrawal from all that caffeine ingestion resulted in a rise in circulating dietary caffeine. Caffeine-induced hormonal and meta- catecholamines, which mobilized FFAs from adipo- bolic responses and exercise endurance were examined to cytes, thus increasing the amount of fat available for determine the effect of habituation and withdrawal in active muscle (10, 14, 22). The ergogenic effect was caffeine users during high-intensity cycling exercise under thought to be a result of utilization of fat and a resulting conditions of placebo or acute caffeine ingestion (6 mg/kg).
sparing of muscle glycogen (14). These concepts weretested into the 1990s (18, 29), but more recent research has failed to support this hypothesis (7, 19).
In humans at rest, Robertson et al. (27) found that moderate prolonged caffeine use was sufficient to Six recreational male athletes agreed to participate in the dampen the caffeine-induced epinephrine response.
study after being informed of the nature of the experiments.
There are few exercise studies (2, 21, 32) that test the Subjects were nonsmokers and had been actively cycling 8750-7587/98 $5.00 Copyright ௠ 1998 the American Physiological Society CAFFEINE, WITHDRAWAL, AND EXERCISE METABOLISM and/or running five times per week for at least 1 yr (n ϭ 5) or five times per week for 3 mo (n ϭ 1). Subjects were 36.7 Ϯ 4.2(SE) yr of age, weighed 75.1 Ϯ 1.6 kg, and had an average The protocol for each trial was identical. Trials were held at daily caffeine consumption from all sources equivalent to the same time of day for each subject and typically started at 761.3 Ϯ 11.8 mg/day [based on self-reporting and using 0900. Before each trial, a venous catheter was inserted into amounts recommended by Conlee (9)]. Their primary source the antecubital vein and was kept patent with a saline of dietary caffeine was from coffee. Each subject signed a infusion. The subject then rested in a supine position for 15 consent form that outlined possible risks of the procedure.
min before any further testing. A resting blood sample of 12 The protocol was approved by the University of Guelph Ethics ml was then collected, and the subject ingested the trial substance in gelatin capsules with water (Ϫ60 min). After 1 hof rest, during which time the subject was allowed to sit or lie quietly, another resting blood sample was obtained (0 min).
Subjects then exercised to exhaustion at 80–85% V Subjects reported to the laboratory before the start of the cycle ergometer. Each subject completed a 5 min warm-up at experiment for an incremental maximum oxygen uptake a lower power output, which was identical for all trials and ˙ O2max) test on a cycle ergometer from which a power output was not considered as part of the total exercise time.
Samples for expired air were taken every 5 min during the was 54.5 Ϯ 3.3 ml · kgϪ1 · minϪ1. They returned for at least one initial 20 min of exercise, and blood samples (12 ml) were additional trial ride of 30-min duration to confirm the power taken at 5 and 20 min after the warm-up period. A final blood ˙ O2max and to habituate and an expired air sample were taken within 2 min before the point of exhaustion. No samples were taken between 20 min Subjects were requested to maintain similar exercise pat- and exhaustion so that subjects could not count samples as a terns throughout the duration of the experiments, to follow crude timing device. Exhaustion was determined by the constant activity patterns for the 3 days before each test, and investigator when cadence could no longer be maintained at a to abstain from exercise 24 h before each trial. They were rate of 90% of the subject’s set rate. When the researchers requested to consume similar diets for 48 h before each thought the subject was close to exhaustion, a sample was experiment, and each maintained a diet record for this period.
taken. If the subject did not demonstrate decreased cadence When they were required to abstain from caffeine (i.e., within 2 min of that sample, another sample was taken, and withdrawal), they were cautioned to avoid sources of methyl- the former was discarded. Water was given ad libitum during xanthines such as tea, coffee, chocolate, cola drinks, and exercise. Subjects did not have access to any indication of caffeine-containing over-the-counter pharmaceuticals, and time after the initial 20-min sampling period during the they were asked to report any deviations from these instruc- tions. For the no-withdrawal trials they were allowed toconsume products containing caffeine up to the morning of the trial. Subjects were requested to consume a small meal2–4 h before the experiment, which was identical for each Expired gas samples were analyzed for fractions of O2 and trial. Dietary consistency was confirmed through self- CO2 with an Applied Electrochemical S-3A O2 analyzer and reported diet records and questioning before each trial.
Sensor Medics LB-2 CO2 detector, respectively. Expired vol- Subjective withdrawal symptoms were recorded for each ume was determined with a Parkinson-Cowan volumeter.
The analyzers were calibrated with gases of known concentra- Seven exercise trials to exhaustion were completed by all tions, previously determined by micro-Scholander technique.
subjects. A minimum of 10 days between all trials was The volume meter was calibrated with a Tissot spirometer.
established to minimize any possible effects of the abstinence Blood samples were immediately separated into two ali- from normal caffeine intake. The first two trials were com- quots: 3 ml were transferred to a nontreated tube for serum, pleted without any withdrawal from dietary caffeine, and and 7 ml were transferred into a sodium heparinized tube.
subjects were assigned randomly either dextrose placebo (Pl Hematocrit was immediately measured in triplicate from the 0d) or caffeine (Caf 0d; 6 mg/kg body wt; Caffeine US latter tube by using high-speed centrifugation. Hemoconcen- Pharmaceutical/Federal Commerce Comission catalog no.
tration occurred in all the exercise samples, but there was no C-0905, A&C American Chemicals). It was believed that the difference between trials. An aliquot of 100 µl heparinized tests under normal habituation would most likely mimic the blood was added to 500 µl of 0.3 M perchloric acid. A solution responses in other comparable studies, and therefore the containing 120 µl of 0.24 M EGTA and reduced glutathione protocol was designed with these tests before withdrawal was was then added to the remaining heparinized whole blood.
commenced. Subsequent exercise trials were conducted after The EGTA and glutathione treated plasma was analyzed periods of either a 2- or 4-day withdrawal from dietary for epinephrine and norepinephrine (NE) concentration by caffeine and are designated as Pl 2d and Pl 4d, for the placebo using HPLC (Waters) as described by Weiker et al. (34).
2- and 4-day withdrawals, respectively, and as Caf 2d and Caf Plasma caffeine was analyzed by using fully automated 4d for the caffeine 2- and 4-day withdrawals, respectively.
HPLC (Waters). For the latter procedure, plasma samples Both the sequence of days of withdrawal and the receipt of were subjected to centrifugal filtration by using Ultrafree-MC caffeine or placebo were assigned in a random, double-blind polysulfone filter units (Millipore UFC3TGC). Filtered plasma manner for all trials. After these experiments all subjects and the internal standard ␤-hydroxyethyltheophylline were participated in a placebo-repeat trial (Pl R) (administered in a injected onto a resolve Radial-Pak cartridge (Waters 84624) single-blind manner) without any period of withdrawal from by using a Radial Compression Module 8 ϫ 10 pressure caffeine as a control to test for a training effect after the 3- to module. Caffeine was measured at 254-nm wavelength and 6-mo period required to complete the trials. At the completion sensitivity range of 0.01 absorbance units full scale. Reagents of each exercise trial, subjects were asked to complete a for standards were obtained from Sigma Chemical.
questionnaire inquiring whether they could determine which The whole-blood acid extracts were analyzed enzymatically drug they had received and to describe the basis on which in triplicate for lactate and glucose as described by Berg- meyer (3). Serum was analyzed enzymatically in triplicate for CAFFEINE, WITHDRAWAL, AND EXERCISE METABOLISM FFAs (26) and glycerol (16). Plasma insulin was analyzed by 6.7 vs. 59.5 Ϯ 8.4 min), and the 4-day withdrawal using 125I radioimmunoassay kit (Diagnostic Products Code-a- (81.5 Ϯ 6.4 vs. 63.6 Ϯ 5.6 min). In contrast to the Pl 0d Count Insulin kit). Diet analysis was completed as described trial, the time to exhaustion in the Pl R trial was not significantly different than in the Caf 0d trial. This increase in time for the Pl R trial is heavily influencedby a single subject whose time increased from 70 to 124 Statistical analysis of respiratory, exercise, and blood data min (Pl 0d vs. Pl R, respectively). When this subject’s was conducted by using repeated-measures analysis of vari- data are removed from the analyses, the Pl R and Caf ance for drug and withdrawal. Bonferroni corrected t-tests 0d trials are significantly different, because all other were used to adjust ␣ levels to limit the possibility of a type I subjects performed similarly in both Pl trials.
error. A one-way analysis of variance was used to test thedifference between Pl 0d and Pl R data as well as Caf 0d and Pl R data. Experimental significance is described as P Ͻ 0.05,and all data are reported as means Ϯ SE. Because of the small Ingestion of caffeine resulted in a significant increase number of subjects, observed power calculations were com- in plasma epinephrine concentration in all trials at pleted and were found to be ϳ0.500 for all nonsignificant exhaustion compared with that of placebo regardless of the days of withdrawal (F ϭ 11.090, P ϭ 0.007; Fig. 2).
There was an effect of withdrawal on NE responses tocaffeine. Caffeine ingestion resulted in significantly There was no significant difference between the Pl 0d elevated plasma NE concentrations over the placebo and the Pl R trials in any of the measured parameters.
conditions at exhaustion in the 2- and 4-day with- Although the original purpose of the Pl R trial was for drawal trials, but NE levels were similar to placebo in use as a comparison with the Pl 0d trial, statistical the no-withdrawal trial (F ϭ 8.793, P ϭ 0.006; Fig. 3).
comparison of the Pl R and Caf 0d data was completed.
These data followed a similar pattern of significance as did the Pl 0d vs. Caf 0d data, with the exception of thetime data. Therefore, the Pl R data will be shown only Insulin concentration declined with exercise, and with respect to time to exhaustion (Fig. 1).
there were no significant differences in any of the trialsafter ingestion of caffeine (data not shown). Initial values for the no-withdrawal trials were 9.0 Ϯ 3.0 and10.6 Ϯ 3.6 µU/ml at Ϫ60 min, which decreased to 2.7 Ϯ Time to exhaustion was significantly increased over 0.4 and 5.5 Ϯ 2.4 µU/ml at exhaustion, for placebo and placebo in all caffeine trials regardless of the period of withdrawal (Fig. 1). Ingestion of caffeine significantlyincreased the time to exhaustion in all subjects after no withdrawal (74.8 Ϯ 8.8 vs. 59.0 Ϯ 3.7 min for caffeinevs. placebo, respectively), the 2-day withdrawal (81.1 Ϯ FFAs. There is a significant effect of caffeine inges- tion on FFA concentrations (F ϭ 25.100, P ϭ 0.004).
This significant increase occurred in the 4-day trialafter caffeine ingestion when FFA concentration in-creased at rest from 0.22 Ϯ 0.04 mM (Ϫ60 min) beforecaffeine ingestion to 0.45 Ϯ 0.12 mM (0 min) comparedwith the Pl 4d data. At no other time or treatment wereFFA concentrations significantly altered by caffeine orwithdrawal (Table 1).
Glycerol. Regardless of whether the treatment was placebo or caffeine, serum glycerol concentration in-creased gradually during the initial exercise period andwas elevated at exhaustion in all trials (F ϭ 46.219, P ϭ0.0001) (Table 1). After the 4-day withdrawal fromcaffeine ingestion, there was an increase in glycerolconcentration compared with that in the placebo trial,but this was not significant.
Glucose. Blood glucose concentration was not altered by either days of withdrawal or caffeine ingestion(Table 2). A low initial glucose concentration at Ϫ60min in the Caf 0d trial was demonstrated in four of the Fig. 1. Time to exhaustion in all exercise trials. Trials are groupedaccording to drug treatment [placebo (Pl) vs. caffeine (Caf; 6 mg/kg six subjects despite their reported similar diet and body wt)] and days of withdrawal [no withdrawal (0 days; 0d) or 2-day activity pattern before experimentation.
(2d) or 4-day withdrawal (4d)]. Pl 0d, initial-placebo, no-withdrawal Lactate. Blood lactate increased in response to exer- exercise trial; Pl R, placebo-repeat, no-withdrawal exercise trial, cise in all trials (Fig. 4). After the 2 days of withdrawal, which was performed on completion of all other withdrawal periods.
acute ingestion of caffeine resulted in a tendency Bars are mean data, and vertical lines indicate SE. a Significantdifference from Pl 0d, P Ͻ 0.05.
toward an increase in lactate concentration at exhaus- CAFFEINE, WITHDRAWAL, AND EXERCISE METABOLISM amounts of residual caffeine may be detected in plasma.
When there was no withdrawal, the initial mean plasmacaffeine concentration was 7.11 Ϯ 2.26 (caffeine) and10.99 Ϯ 3.09 (placebo) µM. In the Pl 0d trial, thecaffeine concentration was significantly higher than inother placebo trials. Despite the higher initial value inthe Caf 0d trial, there was no significant difference inmaximal concentrations measured in the caffeine tri-als.
Expired gases. There was no significant difference found in any of the measured parameters of oxygen Plasma epinephrine concentration during exercise under conditions of no withdrawal (A) and 2-day (B) and 4-day withdrawal(C) from dietary caffeine. Lines are mean data, and vertical bars areSE; n ϭ 6 subjects. Time indicates sampling time: Ϫ60, preingestion;0, 1 h of rest postingestion at start of exercise; 5 and 20, timefrom start of exercise; exhaustion (exh), end of exercise when subjectcould no longer maintain a power output of 85% maximum oxygenuptake. j, Placebo; s, caffeine. * Significant difference from placebo,P Ͻ 0.05.
tion compared with that at Pl 2d, and after the 4-daywithdrawal this trend increased to include increases atboth 20 min and exhaustion. However, this was notstatistically significant.
Fig. 3. Plasma norepinephrine concentrations during exercise under Plasma caffeine. Mean plasma caffeine data are conditions of no withdrawal (A) and 2-day (B) and 4-day withdrawalfrom dietary caffeine (C). Lines are mean data, and vertical bars are presented in Table 3. These data indicate that, after a SE; n ϭ 6 subjects. j, Placebo; s, caffeine. Organization is as in period of even up to 4 days of withdrawal, trace Fig. 2. * Significant difference from placebo, P Ͻ 0.05.
CAFFEINE, WITHDRAWAL, AND EXERCISE METABOLISM Table 1. Serum free fatty acids and glycerol 0.22Ϯ0.04 0.45Ϯ0.12* 0.25Ϯ0.02 0.34Ϯ0.08 0.60Ϯ0.10 Values are means Ϯ SE given in mM for 6 subjects for placebo (Pl) and caffeine (Caf) trials; 0d, no withdrawal; 2d, 2-day withdrawal; 4d,4-day withdrawal. Time points indicate before 4d ingestion (Ϫ60),after 1 h rest (0), after 5 and 20 min of exercise, and at exhaustion(Exh) when power output could no longer be maintained. FFA, freefatty acids. * Significantly different from Pl within same protocol,P Ͻ 0.05.
consumption, carbon dioxide production, V not shown), or respiratory exchange ratio (RER)(Table 4). Each subject achieved ϳ85% V 0.05 ml · kgϪ1 · minϪ1) by the 20-min time point duringexercise as calculated from the initial V maintained this power output until near exhaustion.
Diet. On the basis of self-reported diet records, there were no significant differences between subjects andbetween trials for a given subject with respect to thepercentage of dietary fat, carbohydrate, and protein.
Subjects consumed a mixed diet of 30–35% fat, 50–54%carbohydrate, and 12–14% protein. Subjects reportedthat they maintained the same diet immediately beforeeach trial.
Perception of trial substance. When asked by question- naire to identify which substance they had received,subjects generally correctly identified the trial sub-stances, with some exceptions. One subject was unableto discriminate between caffeine and placebo on mostoccasions (incorrect in 5 of 7 trials). Another subject dididentify caffeine correctly but was unable to definitelyidentify placebo during periods of withdrawal. The Whole-blood lactate concentration during exercise under subjects’ justification for guessing caffeine included conditions of no withdrawal (A) and 2-day (B) and 4-day withdrawal(C) from dietary caffeine. Lines are mean data, and vertical bars are feelings of alertness, less fatigue during exercise, caf- SE; n ϭ 6 subjects. j, Placebo; s, caffeine. Organization is as inFig. 2.
feine-induced diuresis, and talkativeness. The with- drawal symptoms varied in severity among subjectsand between similar withdrawal periods.
DISCUSSION
4.40Ϯ0.57 3.68Ϯ0.28 4.25Ϯ0.26 4.45Ϯ0.37 4.25Ϯ0.50 4.26Ϯ0.57 3.23Ϯ0.53 3.48Ϯ0.38 3.50Ϯ0.52 3.44Ϯ0.47 In this study the effects of short-term withdrawal Ϯ0.41 3.67Ϯ0.47 3.41Ϯ0.14 3.71Ϯ0.21 3.42Ϯ0.28 2.97Ϯ0.53 3.99Ϯ0.54 3.23Ϯ0.56 3.47Ϯ0.43 2.96Ϯ0.62 from dietary caffeine during high-intensity exercise on 3.38Ϯ0.12 3.37Ϯ0.42 3.40Ϯ0.29 3.89Ϯ0.22 3.61Ϯ0.20 hormonal, metabolic, and endurance responses with or 3.53Ϯ0.45 4.31Ϯ0.45 4.12Ϯ0.66 4.62Ϯ0.29 3.55Ϯ0.62 without acute ingestion of caffeine were examined. The Values are means Ϯ SE in mM for 6 subjects.
present study is the first to investigate the effect of CAFFEINE, WITHDRAWAL, AND EXERCISE METABOLISM Table 3. Mean plasma caffeine data Values are means Ϯ SE in µM for 6 subjects. Ingestion of caffeine resulted in significantly greater concentration vs. placebo.
withdrawal from dietary caffeine over the critical 4-day days) and then were tested by using standardized period in which tolerance to caffeine and withdrawal exercise trials. Exercise performance data throughout symptoms are reported (27), and it is unique in the all days of withdrawal in the placebo trials were examination of the influence that prior caffeine use similar, indicating changes in the caffeine trials were a may have on epinephrine and ergogenic responses result of acute caffeine ingestion and were not a product during high-intensity exercise. Under the placebo con- dition, days of withdrawal, i.e., 0, 2, or 4 days, did not In many exercise studies, the pharmacological prop- alter the basic responses in any measured parameters.
erties of caffeine regarding tolerance to the metabolic Withdrawal from caffeine resulted in caffeine-induced effects have not been considered. Adenosine receptors changes in serum FFAs at 4 days and in plasma NE are widely distributed throughout the body in the responses at 2 and 4 days. The significance of the brain, adipose tissue, smooth and cardiac muscle, and changes in concentration of these metabolites after adrenal gland. If caffeine acts primarily as an adenosine- acute caffeine ingestion is uncertain because with- receptor antagonist in vivo, then short-term with- drawal from dietary caffeine did not alter either the drawal should result in significant enhancement (upreg- ergogenic or the epinephrine response.
ulation) (24), suggesting that adenosine-mediated When the exercise literature is reviewed, there is effects will be more pronounced. In contrast to findings inconsistency found regarding the ergogenic effect of in resting subjects, we demonstrate here an increase in caffeine that may be attributable to lack of control of plasma epinephrine in response to exercise and caffeine prior caffeine use in the subjects. In two studies in regardless of the state of habituation or withdrawal.
which a positive ergogenic effect is reported (18, 29), a Robertson et al. (27) found that prior caffeine use 48-h withdrawal from dietary caffeine was used before resulted in attenuation of the caffeine-induced increase testing. In other studies, when prior caffeine use is not in plasma epinephrine concentration, and a 4-day reported, some authors found no effect (6, 13, 28) and period of abstinence was used to restore the expected others a positive response (10, 14, 22). The similar epinephrine increase after acute caffeine ingestion. On longer exhaustion times in the caffeine trials in all the basis of this literature and other research involving subjects reported here suggests that withdrawal from adenosine-receptor-mediated responses (4), we deter- caffeine before testing was not a factor in this variation.
mined that a 2- and a 4-day withdrawal would be The mean time to exhaustion in the Pl R trial com- adequate to observe any metabolic and hormonal pleted in this study was not significantly different from changes that occur during the transition from habitua- that in the Caf 0d as a result of one subject almost tion through withdrawal. The lack of epinephrine re- doubling his exercise time during the Pl R trial vs. the sponse to withdrawal after acute caffeine ingestion Caf 0d. This suggests that variation in this time to reported here both at rest and during exercise may be exhaustion in studies in which a small number of due to the exercise intensity. It appears that the strong subjects were used may have influenced previous re- sympathetic stimulus of exhaustive exercise during sults. To minimize confounding variables, our subjects habituation and withdrawal acts to surmount tolerance regulated their diet and exercise activity for 48 h before to the caffeine stimulus, which contributed to the testing during all phases of withdrawal (0, 2, and 4 uniform rise in plasma epinephrine at exhaustion Values are means Ϯ SE for 6 subjects. RER, respiratory exchange ratio.
CAFFEINE, WITHDRAWAL, AND EXERCISE METABOLISM regardless of dietary caffeine use before experimenta- rather than through secondary stimulation via the An alternative explanation for the changes in epi- The complexity of the metabolic responses to acute nephrine and NE concentrations at exhaustion in the caffeine ingestion during exercise makes dissociation of caffeine trials would include a linear relationship be- the possible causal effects difficult to distinguish. Distri- tween time to exhaustion and increases in plasma bution of adenosine receptors throughout the periph- catecholamines rather than a caffeine effect. In the eral tissues and the central nervous system suggests present study, it is impossible to determine whether the that caffeine may act directly or indirectly through effect on catecholamines is merely a result of a longer multiple mechanisms (4, 17, 25, 31). Additional support duration of exercise. However, in examining the data, for the direct action of caffeine on specific tissues can be epinephrine concentrations are similar between the found in several studies (25, 32). Lopes et al. (25) used Caf 0d trial and the Caf 4d trial, despite the latter electrical stimulation of the adductor pollicis after lasting 7 min longer. The changes in NE are more ingestion of caffeine to dissociate both metabolic and difficult to interpret because of the similarity of time centrally mediated effects from increases in time to between 2- and 4 day trials. Because of the uncertainty fatigue. Subsequent research is needed to determine of interpreting catecholamine data from this study, whether it is peripheral vs. centrally mediated effects further research will be needed to determine the rela- that are significant in the caffeine-mediated ergogenic tionship between caffeine-induced changes in epineph- rine concentration during exercise and time to exhaus- To investigate whether our results could be influ- tion. Regardless, the number of days of withdrawal enced by variations in available plasma concentrations from caffeine did not influence the ergogenic effects of of methylxanthines, the measurements of caffeine con- acute caffeine ingestion, and the mechanism for this centrations before and during exercise in this study may be related to a number of factors.
were used to confirm compliance to the protocol and as These data indicate that acute caffeine ingestion an indication of the similarity of drug stimulus between during short-term withdrawal alters mobilization of trials. Despite high plasma caffeine concentrations in serum FFA. The changes in serum concentrations after the Pl 0d trial (ϳ10 µM), changes in performance did withdrawal from caffeine may not have altered uptake not occur until greater concentrations (Ͼ30 µM) were or oxidation because there was no significant impact on achieved in the caffeine trials. Graham and Spriet (19) RER, but without arteriovenous data this remains report that plasma caffeine concentrations of 18 µM speculative. Our data are in agreement with those (after ingestion of 3 mg/kg caffeine) result in ergogenic reported by Hetzler et al. (21), who found that acute effects. Whether there is a critical concentration be- withdrawal from caffeine did not alter substrate utiliza- tween 10 and 18 µM that represents a threshold of tion during submaximal exercise. However, these inves-tigators limited their study to a 48-h interval to test caffeine activity during exercise is not known.
withdrawal, which we believed was not sufficient be- Withdrawal from dietary caffeine did not alter the cause there is considerable variability in the reported maximal plasma caffeine concentration during exercise time course of symptoms of withdrawal from 12 to 48 h despite the presence of higher initial concentrations in (20). In a study by Biaggioni et al. (4), a 60-h with- the no-withdrawal trial. This is consistent with the drawal was required to alter adenosine-mediated plate- data available regarding caffeine metabolism in the let response to methylxanthines in human subjects.
liver. The cytochrome P-450 isoform 1A2, which repre- This proved to be the case with respect to serum FFA sents the major pathway for caffeine 1-and 7-demethyl- responses in our subjects, in whom there was a signifi- ations (23), is saturable (12), and steady-state concen- cant caffeine effect after a 4-day withdrawal, which would trations were achieved over the time course in the have been missed if only 2 days were investigated.
present study. Factors that would alter the activity of To counteract the possibility of a statistical error due the P450 1A2 enzyme include smoking, oral contracep- to multiple comparisons, the Bonferroni corrected t-test tive use, ingestion of cruciferous vegetables, and physi- was applied, increasing the rigor of acceptance of the cal fitness (5, 33). Subjects in the present experiment null hypothesis. Therefore, the significant changes in did not smoke or use oral contraceptives, and diet both FFA at rest and NE during exercise in the present analysis indicated no use of cruciferous vegetables.
study are likely a result of withdrawal from caffeine.
They maintained the same level of fitness throughout Whether the absence of enhanced substrate utilization the experiment. Therefore, these factors would have would have continued over 4 days in the work of minor, if any, effect on available plasma concentrations Hetzler et al. (21) is not known, and the lack of of caffeine and are unlikely to have influenced findings methylxanthine data in their research makes interpre- in this study. Subjects arrived after a 4-day withdrawal tation of prior caffeine status impossible to establish.
from caffeine with small, but measurable, caffeine However, these data, coupled with the present findings, concentrations, which is consistent with the wide vari- suggest that the mechanism through which caffeine ability in caffeine half-life (1.5–9.5 h) (21). The minor acts to enhance exercise performance may not be linked increase of 15–20% in plasma caffeine concentration in to changes in adipose lipolysis. The increase in lipolysis the Caf 0d vs. the Caf 2d or Caf 4d trials did not may be related to the direct systemic effects of caffeine influence results reported here, which is in agreement ingestion (31) through action on adenosine receptors with Graham and Spriet (19), who found no difference CAFFEINE, WITHDRAWAL, AND EXERCISE METABOLISM in performance between ingestion of 3 vs. 6 mg/kg of unlikely to be through changes in available metabolic substrates or catecholamines but rather is through The ability to discriminate caffeine has been tested in some direct action of caffeine on tissues as yet to be humans and animals (20, 24). Because of the effects of caffeine in humans on arousal and awareness, we The authors acknowledge the technical support of Premila Satha- recorded our subjects’ observations of their trial sub- sivam for analysis of catecholamine and caffeine data.
stances. The majority of subjects correctly identified This study was supported by grants from National Science and caffeine by the effects of arousal and alertness, and, Engineering Research Council of Canada and Sport Canada and byGatorade Sports Science Student Awards.
therefore, it is difficult to claim that they did not know Address for reprint requests: M. van Soeren, NP/CNS ICU, St.
which trial substance had been given. The effect on Joseph’s Health Centre, 268 Grosvenor St., London, Ontario, Canada their performance, therefore, may have been influenced N6A 4V2 (E-mail: mvansoer@julian.uwo.ca).
in some way by knowledge that they had received Received 20 August 1997; accepted in final form 1 June 1998.
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Report written by: Anne-Charlotte Honoré, Milena Izmirlieva, Cameron Lockwood, Gaelle Marinoni, Tania Rodrigues, Ben Shankland and Sophia Walker. Under the supervision of Gaelle Marinoni: Project ManagerStudy Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1Study MethodologyI. Research . . . . . . . . . . . .

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Initially, some philosophers such as G. E. Moore and R.M. Hare firstly introduces the idea of supervenience in ethics. Later, the idea of supervenience is also used in the philosophy of mind, and Donald Davison is perhaps the first philosopher who introduces supervenience into the discussion of the mind-body problem. In ethics, philosophers discuss whether ethical properties supervene on non-e

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