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PubMed2005

Caffeine improves endurance in 75-yr-old citizens: a randomized, double-blind, placebo-controlled, crossover study.

This study investigated the effect of caffeine on physical performance in healthy citizens aged > or =70 yr. The randomized, double-blind, placebo-controlled, crossover study was conducted in 15 men and 15 women recruited by their general practitioner. Participants abstained from caffeine for 48 h and were randomized to receive one capsule of placebo and then caffeine (6 mg/kg) or caffeine and then placebo with 1 wk in between. One hour after intervention, we measured reaction and movement times, postural stability, walking speed, cycling at 65% of expected maximal heart rate, perceived effort during cycling, maximal isometric arm flexion strength, and endurance. Analysis was by intention to treat, and P < 0.05 was regarded as significant. Caffeine increased cycling endurance by 25% [95% confidence interval (CI): 13-38; P = 0.0001] and isometric arm flexion endurance by 54% (95% CI: 29-83; P = 0.0001). Caffeine also reduced the rating of perceived exertion after 5 min of cycling by 11% (95% CI: 5-17; P = 0.002) and postural stability with eyes open by 25% (95% CI: 2-53; P = 0.03). Caffeine ingestion did not affect muscle strength, walking speed, reaction, and movement times. At the end of the study, 46% of participants correctly identified when they received caffeine and placebo. Caffeine increased exercise endurance in healthy citizens aged > or =70 yr, but the participants' reasons for stopping the test may have varied between subjects, as the cycling test was done at approximately 55% of maximal oxygen consumption. Further studies are required to investigate whether caffeine can be utilized to improve the physical performance of elderly citizens.

Administration, Oral↗
PubMed1976

Rhythmic hyperpolarizations and depolarization of sympathetic ganglion cells induced by caffeine.

Superfusion of the isolated sympathetic ganglion of the bullfrog with a caffeine-containing (1-6 mM) solution caused in many cells an initial slow hyperpolarization which was followed by a subliminal depolarization interruped by rhythmic hyperpolarizations. A hyperpolarization, similar to one of the rhythmic hyperpolarizations, could be triggered by an action potential in the presence of caffeine. The action potential itself was not markedly affected by caffeine except for its afterhyperpolarization which was prolonged. All these caffeine-induced hyperpolarizations were associated with a marked reduction of the membrane resistance, their amplitude was increased in a K+-free solution and decreased in a high-K+ solution, and their polarity was reversed at the same level at which the afterhyperpolarization was also inverted. This reversal level was not altered by omission of Na+ or C1- from the external medium. These hyperpolarizations were reversibly abolished by depletion of external Ca2+ or replacement of external Ca2+ by Mg2+. Excess of external Ca2+ caused a shortening of the interval between rhythmic hyperpolarizations. Furthermore, iontophoretic injection of EDTA into the cytoplasm markedly depressed the initial caffeine hyperpolarizatin and abolished both the rhythmic and evoked caffeine hyperpolarizations. The caffeine-induced depolarization was not affected by omission of external Cl-. It was decreased in a Na+-free medium, but completely eliminated by omission of both Na+ and Ca2+ from the external medium. Tetrodotoxin did not impair the production of the initial and the rhythmic hyperpolarizations. A strong depolarizing pulse could evoke a typical hyperpolarizing response in the presence of this compound. Dibutyryl cyclic AMP, d-tubocurarine, atropine, and phenoxybenzamine were without effect on the caffeine-induced hyperpolarizations and depolarization. It was concluded that each caffeine-induced hyperpolarization is the result of an increased K+ permeability, which is probably caused by a rise in the internal Ca2+ concentration. It was also concluded that the caffeine-induced depolarization is due to an increased membrane permeability to Ca2+ and Na+.

Animals↗
PubMed2001

Ketoprofen-induced cyclooxygenase inhibition in renal medulla and platelets of rats treated with caffeine.

It has been suggested that caffeine can augment analgesic activity and aggravate side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of the present study was to investigate a possible interaction between ketoprofen and caffeine on prostaglandin (PG) biosynthesis and cyclooxygenase (COX) mRNA expression in the rat renal medulla ex vivo. Treatment of rats with ketoprofen (60 min before) resulted in a dose-dependent (estimated ID(50) 0.3 mg/kg p.o.) reduction of PGE(2) biosynthesis in renal medulla ex vivo. Ketoprofen (0.3 mg/kg)-induced inhibition of PGE(2) biosynthesis was stable between 30 and 180 min and still detectable 300 min after drug administration. Caffeine (10 mg/kg) did not cause a detectable effect on its own, nor did it significantly affect ketoprofen-induced inhibition of renal medullary PGE(2) biosynthesis. Similar results were obtained with repeated daily drug administration for 1 week: there was no significant effect of caffeine on ketoprofen-induced inhibition of renal medullary PGE(2) biosynthesis. The absence of significant caffeine effects on ketoprofen-induced inhibition of renal medullary PGE(2) biosynthesis was paralleled by experiments showing no significant effect of caffeine on ketoprofen-induced inhibition of platelet thromboxane (TX)B(2) biosynthesis. Additional experiments showed increased COX-2 mRNA expression in the renal medulla 60 min after ketoprofen administration, that was not significantly influenced by concomitant caffeine treatment. Treatment of rats with ketoprofen for 1 week had no significant effects on COX-2 mRNA expression. The present results show that ketoprofen caused inhibition of PGE(2) biosynthesis in the rat renal medulla ex vivo with a potency similar to that reported for in vivo models suggesting that the ex vivo approach is a valid model to test a possible interference of caffeine with ketoprofen-induced COX inhibition. The absence of detectable effects of caffeine on time course or magnitude of ketoprofen-induced suppression of PGE(2) biosynthesis in this model indicates, therefore, that possible adverse actions of co-administered caffeine on renal function are not related to interference with renal COX inhibition.

Animals↗
PubMed1991

Interaction between caffeine and zinc on brain in newborn rats.

The purpose of this study was to determine whether adding zinc to the caffeine-supplemented diet of dams during gestation and lactation would affect brain development in newborn rats. On day 9 of gestation, dams of group 1 were fed to a 20% protein diet as a control. Dams of group 2 were fed a 20% protein diet supplemented with caffeine. Dams of group 3 were fed a 20% protein diet supplemented with caffeine and zinc. The amount of caffeine added to the maternal diet was 2 mg/100 g of body weight. The amount of zinc chloride added to diet was 0.6 g/kg of diet. At birth, 8 randomly selected pups from each group were assigned to each dam of the respective group and were continuously fed the same diet. On day 15, the pups were killed and brains were removed. Zinc, protein, DNA, alkaline phosphatase activity and cholesterol contents were measured. Milk and maternal and neonatal blood were collected to determine caffeine levels. There was a significant correlation between the milk caffeine and brain caffeine concentrations in group 3. A significant correlation between the neonatal plasma caffeine and brain caffeine concentrations was observed in groups 2 and 3. There was no correlation between neonatal brain weight and zinc content per brain in each group. The correlation between neonatal brain weight and alkaline phosphatase activity was significant in groups 1 and 3. The neonatal zinc content and concentration of group 2 was less than that of group 1. The DNA content and concentration of group 3 was greater than that of either groups 1 or 2. Supplementation of zinc to the caffeine-added diet could restore the brain zinc levels observed in brains of newborn rats.

Alkaline Phosphatase↗
PubMed2002

Coffee acutely increases sympathetic nerve activity and blood pressure independently of caffeine content: role of habitual versus nonhabitual drinking.

BACKGROUND: Coffee is the most abundantly consumed stimulant worldwide. However, its cardiovascular safety remains controversial. Possible health hazards have been related to its main ingredient, caffeine. Activation of the sympathetic nervous system by coffee may enhance cardiovascular risk; however, it is unclear whether this effect of coffee is related to caffeine or other substance(s) also contained in decaffeinated coffee. METHODS AND RESULTS: In 15 healthy volunteers (6 habitual and 9 nonhabitual coffee drinkers) arterial blood pressure (BP), heart rate, and muscle sympathetic nervous activity (MSA) were continuously recorded before and after drinking a triple espresso or a decaffeinated triple espresso or after intravenous administration of caffeine (250 mg) or placebo (saline) in the same subjects. There was a significant time x condition interaction for the intravenous caffeine and placebo conditions for MSA, with caffeine showing a significant increase in MSA at 60 minutes (53.2+/-14.1% total activity) and the placebo group showing no effect. A similar significant time effect was found for coffee drinking (54.1+/-22.5% total activity). Habitual and nonhabitual coffee drinkers demonstrated similar changes in MSA and BP after intravenous caffeine, whereas coffee drinking increased BP in nonhabitual drinkers only, despite comparable increases of MSA and plasma caffeine levels. Nonhabitual coffee drinkers showed similar activation of MSA and BP after caffeine infusion, coffee, or decaffeinated coffee. CONCLUSIONS: Acutely, coffee and caffeine induced comparable increases in MSA and BP in nonhabitual coffee drinkers, whereas habitual coffee drinkers exhibited lack of BP increase despite MSA activation to coffee. Because decaffeinated coffee also increases BP and MSA in nonhabitual drinkers, ingredients other than caffeine must be responsible for cardiovascular activation.

Administration, Oral↗
PubMed2003

Caffeine and central noradrenaline: effects on mood, cognitive performance, eye movements and cardiovascular function.

There have been numerous studies on the effects of caffeine on behaviour and cardiovascular function. It is now important to clarify the mechanisms that underlie such effects, and the main objective of the present study was to investigate whether changes in central noradrenaline underlie some of the behavioural and cardiovascular effects of caffeine. This was examined using a clonidine challenge paradigm. Twenty-four healthy volunteers were assigned to one of four conditions: (i) clonidine/caffeine; (ii) clonidine/placebo; (iii) placebo/caffeine: (iv) placebo/placebo. Baseline measurements of mood, cognitive performance, saccadic eye movements and cardiovascular function were recorded. Subsequently, volunteers were given either clonidine (200 microg) or placebo and consumed coffee containing caffeine (1.5 mg/kg) or placebo. The test battery was then repeated 30 min, 150 min and 270 min later. A second cup of coffee (with the same amount of caffeine as the first) was consumed 120 min after the first cup. The results showed that clonidine reduced alertness, impaired many aspects of performance and slowed saccadic eye movements; caffeine removed many of these impairments. Both clonidine and caffeine influenced blood pressure (clonidine reduced it, caffeine raised it) but the effects appeared to be independent, suggesting that separate mechanisms were involved. In addition, there were some behavioural effects of caffeine that were independent of the clonidine effect (e.g. effects on speed of encoding of new information) and these may reflect other neurotransmitter systems (e.g cholinergic effects). Overall, the results suggest that caffeine counteracts reductions in the turnover of central noradrenaline. This mechanism may underlie the beneficial effects of caffeine seen in low alertness states.

Adolescent↗
PubMed1992

The effect of brassica vegetable consumption on caffeine metabolism in humans.

Ten healthy volunteers were used in two studies investigating the effect of short-term Brassica consumption on caffeine metabolism. In the first study volunteers were given three Brassica-containing meals, the last one 3 h prior to caffeine administration. In the second study volunteers were given two Brassica-containing meals and then fasted overnight before caffeine administration. In both studies the mean plasma half-life of caffeine was reduced by approximately 20% following a Brassica diet, suggesting that Brassica vegetables stimulate caffeine metabolism. When caffeine was given 3 h after the last meal, plasma caffeine concentrations over 6 h, were increased by up to 27% on the Brassica diet compared to controls. This may be due to a transient increased permeability of the intestine to caffeine, immediately following Brassica consumption. This effect was not seen in the second study where there was a 12-h period between the last meal and caffeine administration. There was large interindividual variation in the effect of the Brassica diet on caffeine metabolism.

Administration, Oral↗
PubMed1995

Topographic quantitative EEG measures of alpha and theta power changes during caffeine withdrawal: preliminary findings from normal subjects.

Neurophysiological consequences of withdrawal from caffeine are poorly understood. In particular, quantitative studies of EEG changes that may occur during the period of caffeine abstinence in caffeine dependent individuals have not been reported. In this pilot study, 13 physically- and psychiatrically-normal caffeine users were asked to abstain from caffeine for a period of 4 days. Quantitative EEGs were obtained prior to stopping caffeine and on Days 1, 2, and 4 of the caffeine abstinence period. Results indicated that significant increases in alpha and theta absolute power accompany the caffeine withdrawal process with return to the pre-abstinent EEG levels when caffeine usage is resumed. The implications of these findings are discussed with special reference to the possible need to control for the variable of caffeine usage in quantitative EEG studies of other phenomena.

Adolescent↗
PubMed1995

The effect of long term caffeine treatment on hypoxic-ischemic brain damage in the neonate.

There is considerable concern over the widespread use of caffeine during and after pregnancy. We have therefore examined the effect of perinatal caffeine use on the vulnerability of the immature brain to hypoxic ischemia (HI). Rat pups were exposed to caffeine during the first 7 d after birth by addition of a low or a high dose (0.3 or 0.8 g/L) of caffeine to the drinking water of their dams. At 7 d the pups were exposed to unilateral carotid occlusion+exposure to 7.70% oxygen for 100 min. The extent of HI brain damage was evaluated 2 wk after the insult. The effects of caffeine on A1 and A2a receptors, A1 mRNA and A2a mRNA, were examined by receptor autoradiography and in situ hybridization. Caffeine, theobromine, theophylline, and paraxanthine were analyzed in plasma of separate animals. Exposure to caffeine reduced HI brain damage from 40.3 +/- 3.2% in controls to 29.8 +/- 4.0% (p < 0.05) in low dose and 33.7 +/- 3.9% (NS) in the high dose group. The A1 receptor density measured as [3H]-1,3-dipropyl-8-cyclopentyl xanthine ([3H]-DPCPX) binding was not significantly affected after low dose caffeine but increased in the brain of rat pups in the high dose group. The A2a receptor density measured as [3H]-2[p-(2-carbonylethyl)-phenethylamino]-5'-N- ethylcarboxamidoadenosine ([3H]-CGS 21680) binding and the expression of A1 mRNA and A2a mRNA were not altered by caffeine treatment. In conclusion, low dose caffeine exposure (plasma levels corresponding to umbilical cord plasma in newborns of coffee-consuming mothers) reduced HI brain damage by 30% in 7-d-old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Effects of caffeine on prolonged intermittent-sprint ability in team-sport athletes.

PURPOSE: Caffeine can be a powerful ergogenic aid for the performance of prolonged, submaximal exercise. Little evidence, however, supports an ergogenic effect of caffeine on intermittent-sprint performance. Hence, this study was conducted to examine the effects of acute caffeine ingestion on prolonged intermittent-sprint performance. METHODS: Using a double-blind, placebo-controlled design, 10 male team-sport athletes (amateur level, VO2peak 56.5 +/- 8.0 mL x kg(-1) x min(-1)) completed two exercise trials, separated by 7 d, 60 min after ingestion of either 6 mg x kg(-1) caffeine or placebo. The exercise trial was performed on a front-access cycle ergometer and consisted of 2 x 36-min halves, each composed of 18 x 4-s sprints with 2-min active recovery at 35% VO2peak between each sprint. Urinary caffeine levels were measured after exercise. RESULTS: The total amount of sprint work performed during the caffeine trial was 8.5% greater than that performed during the placebo trial in the first half (75,165.4 +/- 3,902.9 vs 69,265.6 +/- 3,719.7 J, P < 0.05), and was 7.6% greater in the second half (73,978.7 +/- 4,092.6 vs 68,783.2 +/- 3,574.4 J, P < 0.05). Similarly, the mean peak power score achieved during sprints in the caffeine trial was 7.0% greater than that achieved during the placebo trial in the first half (1330.9 +/- 68.2 vs 1244.2 +/- 60.7 W, P < 0.05), and was 6.6% greater in the second half (1314.5 +/- 68.4 vs 1233.2 +/- 59.9 W, P < 0.05). Urinary caffeine levels following the caffeine trial ranged from 3.5 to 9.1 microg x mL(-1) (6.9 +/- 0.6 microg x mL(-1)). CONCLUSION: This study revealed that acute caffeine ingestion can significantly enhance performance of prolonged, intermittent-sprint ability in competitive, male, team-sport athletes.

Adolescent↗
PubMed2001

Effect of caffeine on oxygen consumption and metabolic rate in very low birth weight infants with idiopathic apnea.

OBJECTIVE: Methylxanthines are among the most commonly prescribed drugs in neonatal intensive care. This study evaluates the effect of caffeine on oxygen consumption and metabolic rate in premature infants with idiopathic apnea. METHODS: Eighteen preterm infants at gestational ages from 28 to 33 weeks and birth weights of 890 to 1680 g were enrolled in the study. Nine preterm infants received caffeine therapy, and 9 served as a control group. Oxygen consumption and energy expenditure were examined before, during, and after caffeine treatment. RESULTS: Oxygen consumption increased significantly from 7.0 +/- 0.9 before caffeine to 8.8 +/- 0.7 mL/kg/min after 48 hours of caffeine therapy, and energy expenditure increased from 2.1 +/- 0.3 to 3.0 +/- 0.2 kcal/kg/hour. During the observation period of 4 weeks of caffeine treatment, oxygen consumption increased significantly in the caffeine group compared with the control patients. In the caffeine group, a lower environmental temperature was sufficient to maintain a normal body temperature. With similar caloric intake in both groups during the study period, daily weight gain in the control group was significantly higher (21 +/- 4 vs 42 +/- 2 g/d). None of the other parameters recorded changed during caffeine therapy. CONCLUSION: Long-term administration of caffeine in preterm infants is associated with an increase in oxygen consumption and with a reduction of weight gain. This may have implications for clinical practice as nutritional regimens need to be adjusted during this therapy.

Apnea↗
PubMed2001

Evaluation of electrocardiographic and hemodynamic effects of caffeine with acute dosing in healthy volunteers.

STUDY OBJECTIVE: To evaluate the effects of moderate, single-dose caffeine consumption on electrocardiographic variables: PR, QRS, QT, QTc, and RR intervals, and QT and QTc interval dispersion. Effects of caffeine on blood pressure and heart rate also were evaluated. DESIGN: Randomized, double-blind, placebo-controlled, crossover study. SETTING: University school of pharmacy. PATIENTS: Ten healthy volunteers aged 17 years or older. INTERVENTION: Participants abstained from caffeinated products for at least 2 days before the study began and were randomly designated to receive placebo or caffeine 400 mg on various days. For each of the study phases, a baseline 12-lead electrocardiogram (ECG) was performed and a subsequent 12-lead ECG performed 3 hours after ingesting the study drug. Blood pressure readings were taken with each ECG. MEASUREMENTS AND MAIN RESULTS: No significant changes in any intragroup or intergroup electrocardiographic variables occurred. Caffeine increased blood pressure (systolic blood pressure [SBP]/diastolic blood pressure [DBP]) from 118+/-5/75+/-6 mm Hg to 128+/-8/77+/-7 mm Hg versus baseline (p=0.0022 and p=0.0368 for SBP and DBP, respectively). After drug dosing, SBP in the caffeine group was significantly higher than in the placebo group (128+/-8 mm Hg versus 119+/-7 mm Hg, p=0.0174). CONCLUSION: Moderate caffeine consumption by healthy young adults does not acutely affect PR, QRS, QT, QTc, and RR intervals, or QT and QTc interval dispersion. Caffeine-naive subjects experienced persistent elevations in SBP and DBP 3 hours after caffeine ingestion, indicating that longer caffeine abstinence than that which is recommended is necessary for blood pressure determination in the clinical setting.

Administration, Oral↗
PubMed2002

Caffeine eliminates gamma-ray-induced G2-phase delay in human tumor cells but not in normal cells.

It has been known for many years that caffeine reduces or eliminates the G2-phase cell cycle delay normally seen in human HeLa cells or Chinese hamster ovary (CHO) cells after exposure to X or gamma rays. In light of our recent demonstration of a consistent difference between human normal and tumor cells in a G2-phase checkpoint response in the presence of microtubule-active drugs, we examined the effect of caffeine on the G2-phase delays after exposure to gamma rays for cells of three human normal cell lines (GM2149, GM4626, AG1522) and three human tumor cell lines (HeLa, MCF7, OVGI). The G2-phase delays after a dose of 1 Gy were similar for all six cell lines. In agreement with the above-mentioned reports for HeLa and CHO cells, we also observed that the G2-phase delays were eliminated by caffeine in the tumor cell lines. In sharp contrast, caffeine did not eliminate or even reduce the gamma-ray-induced G2-phase delays in any of the human normal cell lines. Since caffeine has several effects in cells, including the inhibition of cAMP and cGMP phosphodiesterases, as well as causing a release of Ca(++) from intracellular stores, we evaluated the effects of other drugs affecting these processes on radiation-induced G2-phase delays in the tumor cell lines. Drugs that inhibit cAMP or cGMP phosphodiesterases did not eliminate the radiation-induced G2-phase delay either separately or in combination. The ability of caffeine to eliminate radiation-induced G2-phase delay was, however, partially reduced by ryanodine and eliminated by thapsigargin, both of which can modulate intracellular calcium, but by different mechanisms. To determine if caffeine was acting through the release of calcium from intracellular stores, calcium was monitored in living cells using a fluorescent calcium indicator, furaII, before and after the addition of caffeine. No calcium release was seen after the addition of caffeine in either OVGI tumor cells or GM2149 normal cells, even though a large calcium release was measured in parallel experiments with ciliary neurons. Thus it is likely that caffeine is eliminating the radiation-induced G2-phase delay through a Ca(++)-independent mechanism, such as the inhibition of a cell cycle-regulating kinase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1992

Low-dose caffeine discrimination and self-reported mood effects in normal volunteers.

A caffeine versus placebo discrimination procedure was used to determine the lowest caffeine dose that could produce discrimination and self-reported mood effects in normal volunteers. During daily sessions under double-blind conditions, caffeine-abstinent subjects orally ingested a capsule containing 178 mg caffeine or placebo. Before beginning discrimination training, the compounds were identified to subjects by letter codes. Fifteen, 30, and 45 min after capsule ingestion, subjects guessed the capsule's letter code. Correct guesses at 45 min earned money. After each session, subjects received a supplementary capsule containing caffeine or placebo to ensure that, within each phase of the study, subjects received the same daily dose of caffeine equal to the training dose. Five of the 15 subjects acquired the caffeine versus placebo discrimination within the first 20 sessions (greater than or equal to 75% correct); 6 other subjects acquired the discrimination with additional training. Nine subjects who acquired the discrimination were subsequently trained at progressively lower caffeine doses. In general, the lowest dose to produce discrimination (greater than or equal to 75% correct) was also the lowest dose to produce self-reported mood effects: 4 subjects showed discrimination and self-reported mood effects at 100 mg caffeine, 2 at 56 mg, 1 at 32 mg, and 1 at 18 mg. One of these subjects also showed self-reported mood effects at 10 mg. The present study documents discriminative stimulus and self-reported mood effects of caffeine at doses below those previously shown to affect any behavior in normal volunteers.

Adult↗
PubMed1995

Pharmacological rationale for the clinical use of caffeine.

Caffeine is widely consumed in beverages to obtain mild CNS stimulant effects. Long term use produces tolerance to some of the pharmacological effects. Withdrawal of caffeine, even from moderate intake levels, can produce symptoms such as headache, fatigue and anxiety. Caffeine is used therapeutically in combination with ergotamine for migraine headaches and in combination with nonsteroidal anti-inflammatory drugs in analgesic formulations. Caffeine alone is used as a somnolytic, to treat various headache conditions, respiratory depression in neonates, postprandial hypotension and obesity, and to enhance seizure duration in electroconvulsive therapy. In some headache and in pain paradigms, caffeine may produce direct adjuvant analgesic properties, while in other headache conditions (perioperative, postdural puncture) caffeine may be effective by alleviating a manifestation of caffeine withdrawal. Other uses, such as to promote wakefulness, for respiratory stimulation and seizure prolongation, rely on central stimulant properties of caffeine. Effects of caffeine on the vasculature may contribute to the relief of some headaches and in postprandial hypotension. Blockade of methylxanthine-sensitive adenosine receptors is the currently accepted mechanism of action of caffeine.

Animals↗
PubMed2004

Caffeine and ephedrine: physiological, metabolic and performance-enhancing effects.

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 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, 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 demanding efforts, some sporadic enhancements have indeed been shown. On the other 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.

Adrenergic Agents↗
PubMed1987

Effects of caffeine on gluconeogenesis and urea synthesis induced by alpha-adrenergic stimulation in suspensions of rat hepatocytes.

Effects of caffeine on gluconeogenesis and urea synthesis of rat isolated hepatocytes were investigated in the presence of hormonal agonists. Phenylephrine at 10 microM stimulated 1.7-fold gluconeogenesis and 1.9-fold (compared to control) urea synthesis from 4 mM glutamine. Stimulative effects of caffeine in the range from 0.1 to 10 mM were biphasic depending on its concentration, and it showed maxima at about 1 mM. Caffeine at 1 mM stimulated 2.1-fold gluconeogenesis and 2.4-fold urea synthesis. Caffeine without phenylephrine did not stimulate both syntheses. These effects of caffeine and phenylephrine diminished in the absence of extracellular Ca2+. Results on uptake of 45Ca2+ into hepatocytes and change in quin-2 fluorescence indicated that phenylephrine induced Ca2+ influx into the cell and consequently increased the intracellular Ca2+ concentration, [Ca2+], and that the addition of caffeine did not further stimulate the effect of phenylephrine on [Ca2+]. Therefore, we suggest that stimulation of gluconeogenesis and urea synthesis by phenylephrine is due to increase in [Ca2+]. Since caffeine is known to inhibit phosphodiesterase, the additional stimulation of both syntheses by caffeine plus phenylephrine may be due to the synergistic effect of increases in cAMP and [Ca2+]. The increase in the rates of gluconeogenesis and urea synthesis similarly depended on the caffeine concentration. Furthermore, the ratio of [acetoacetate]/[3-OH-butyrate] which shows intramitochondrial redox state, also depended on the caffeine concentration, indicating a possible coupling of the redox function of mitochondria with [Ca2+].

Adrenergic alpha-Agonists↗
PubMed2001

Caffeine ingestion decreases glucose disposal during a hyperinsulinemic-euglycemic clamp in sedentary humans.

The purpose of this investigation was to examine the effect of caffeine (an adenosine receptor antagonist) on whole-body insulin-mediated glucose disposal in resting humans. We hypothesized that glucose disposal would be lower after the administration of caffeine compared with placebo. Healthy, lean, sedentary (n = 9) men underwent two trial sessions, one after caffeine administration (5 mg/kg body wt) and one after placebo administration (dextrose) in a double-blind randomized design. Glucose disposal was assessed using a hyperinsulinemic-euglycemic clamp. Before the clamp, there were no differences in circulating levels of methylxanthines, catecholamines, or glucose. Euglycemia was maintained throughout the clamp with no difference in plasma glucose concentrations between trials. The insulin concentrations were also similar in the caffeine and placebo trials. After caffeine administration, glucose disposal was 6.38 +/- 0.76 mg/kg body wt compared with 8.42 +/- 0.63 mg/kg body wt after the placebo trial. This represents a significant (P < 0.05) decrease (24%) in glucose disposal after caffeine ingestion. In addition, carbohydrate storage was 35% lower (P < 0.05) in the caffeine trial than in the placebo trial. Furthermore, even when the difference in glucose disposal was normalized between the trials, there was a 23% difference in the amount of carbohydrate stored after caffeine administration compared with placebo administration. Caffeine ingestion also resulted in higher plasma epinephrine levels than placebo ingestion (P < 0.05). These data support our hypothesis that caffeine ingestion decreases glucose disposal and suggests that adenosine plays a role in regulating glucose disposal in resting humans.

Administration, Oral↗