Acute effects of caffeine injection on neutral amino acids and brain monoamine levels in rats

The injection of caffeine (100 mg/kg, i.p.) into male rats acutely increased brain levels of trytophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). Blood levels of glucose, nonesterified fatty acids (NEFA) and insulin also increased, while those of the aromatic and branched-chain amino acids fell. Serum tryptophan levels either did not fall, or increased. Consequently, the serum ratio of trypthopahn to the sum of other large neutral amino acids (LNAA) increased. Less consistently noted were increases in serum free tryptophan levels. Brain tyrosine levels were not appreciably altered by caffeine, nor was the serum tyrosine ratio. In dose-response studies, 25 mg/kg of caffeine was the minimal effective dose needed to raise brain tryptophan, but only the 100 mg/kg dose elevated all three indoles in brain. In no experiments did caffeine, at any time or dose, alter brain levels of dopamine or norepinephrine. Caffeine thus probably raises brain tryptophan levels by causing insulin secretion, and thereby changing plasma amino acid levels to favor increased tryptophan uptake into brain. The rises in brain 5-HT and 5-HIAA may follow from the increase in brain tryptophan, although further data are required clearly to establish such a mechanism.     

24h withdrawal following repeated administration of caffeine attenuates brain serotonin but not tryptophan in rat brain: Implications for caffeine-induced depression

Caffeine injected at doses of 20, 40 and 80 mg/kg increased brain levels of tryptophan, 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in rat brain. In view of a possible role of 5-HT in caffeine-induced depression the effects of repeated administration of high doses of caffeine on brain 5-HT metabolism are investigated in rats. Caffeine was injected at doses of 80 mg/kg daily for five days. Control animals were injected with sahne daily for five days. On the 6th day caffeine (80 mg/kg) injected to 5 day sahne injected rats increased brain levels of tryptophan, 5-HT and 5-HIAA. Plasma total tryptophan levels were not affected and free tryptophan increased. Brain levels of 5-HT and 5-HIAA but not tryptophan decreased in 5 day caffeine injected rats injected with sahne on the 6th day. Plasma total and free tryptophan were not altered hi these rats. Caffeine-induced increases of brain tryptophan but not 5-HT and 5-HIAA were greater in 5 day caffeine than 5 day sahne injected rats. The findings are discussed as repeated caffeine administration producing adaptive changes in the serotonergic neurons to decrease the conversion of tryptophan to 5-HT and this may precipitate depression particularly in conditions of caffeine withdrawal.     

Cross-tolerance studies between caffeine and (-)-N6-(phenylisopropyl)-adenosine (PIA) in mice

Chronic administration of caffeine to mice (1 mg/ml in drinking water X 14 d) led to a downward shift in the dose-response curve for the locomotor effects of caffeine. Caffeine was also less effective as an antagonist against (-)-(N6-phenylisopropyl)-adenosine (PIA)-induced analgesia in the tail flick assay in these animals. The dose-response curves of PIA for both analgesia and locomotor depression were shifted to the left in animals chronically administered caffeine. In mice chronically administered PIA (1 mg/kg/d X 14 d), the dose-response curves of PIA for both analgesia and locomotor depression were shifted to the right. The dose-response curve for the locomotor effects of caffeine was shifted to the left, and caffeine exhibited greater antagonist activity against the analgesic action of PIA in these animals. There was no change in the Kd or Bmax values of either 3H-PIA or 3H-diethylphenylxanthine (DPX, a potent adenosine receptor antagonist) in mice chronically administered PIA. The Bmax values for both 3H-PIA and 3H-DPX were significantly increased, while the Kd values were not changed in mice chronically administered caffeine. There was no detectable change in the brain levels of either PIA or caffeine in animals chronically treated with either drug. The results demonstrate that chronic administration of caffeine increases the sensitivity of mice to the actions of PIA and vice versa, providing supportive evidence for the interaction of these drugs at the same receptor, which is probably an adenosine receptor.     

Incorporation of caffeine into a quantitative model of fatigue and sleep

A recent physiologically based model of human sleep is extended to incorporate the effects of caffeine on sleep-wake timing and fatigue. The model includes the sleep-active neurons of the hypothalamic ventrolateral preoptic area (VLPO), the wake-active monoaminergic brainstem populations (MA), their interactions with cholinergic/orexinergic (ACh/Orx) input to MA, and circadian and homeostatic drives. We model two effects of caffeine on the brain due to competitive antagonism of adenosine (Ad): (i) a reduction in the homestatic drive and (ii) an increase in cholinergic activity. By comparing the model output to experimental data, constraints are determined on the parameters that describe the action of caffeine on the brain. In accord with experiment, the ranges of these parameters imply significant variability in caffeine sensitivity between individuals, with caffeine's effectiveness in reducing fatigue being highly dependent on an individual's tolerance, and past caffeine and sleep history. Although there are wide individual differences in caffeine sensitivity and thus in parameter values, once the model is calibrated for an individual it can be used to make quantitative predictions for that individual. A number of applications of the model are examined, using exemplar parameter values, including: (i) quantitative estimation of the sleep loss and the delay to sleep onset after taking caffeine for various doses and times; (ii) an analysis of the system's stable states showing that the wake state during sleep deprivation is stabilized after taking caffeine; and (iii) comparing model output successfully to experimental values of subjective fatigue reported in a total sleep deprivation study examining the reduction of fatigue with caffeine. This model provides a framework for quantitatively assessing optimal strategies for using caffeine, on an individual basis, to maintain performance during sleep deprivation.     

Abolition of ventilatory response to caffeine in chemodenervated lambs

In this study we have evaluated the role of the peripheral chemoreceptors in the ventilatory response to caffeine at a dose currently used in human infants for treatment of central apneas (10 mg/kg). Twelve lambs were studied; six had carotid body denervation (CBD) and six had a sham denervation (intact). The denervation was done the 2nd wk of life, and the study of the response to caffeine infusion was carried out at a mean age of 82 days. The awake and nonsedated animals received 10 mg/kg of caffeine, and caffeine blood levels were, respectively, 8.8 and 9.0 mg/l in the intact and in the CBD lambs. The intact lambs responded to caffeine by a significant immediate increase in minute ventilation (VE) of 46% from 274 to 400 ml X min-1 X kg-1 (P less than 0.001), 1 min after caffeine infusion. This response rapidly faded, but VE was still increased at 2 h, 314 ml X min-1 X kg-1. The increase in ventilation was brought about by a change in mean inspiratory flow (VT/TI), which increased from 9.9 to 14.0 ml X s-1 X kg-1 within 1 min (P less than 0.01); VT/TI was still increased at 11.2 ml X s-1 X kg-1 2 h later. In contrast, for the CBD lambs there was no response to caffeine infusion as measured by VE or VT/TI. We conclude that bolus caffeine infusion produces a rapid response in VE followed by a fall in VE that remained above base line until at least 2 h postinfusion, and the intact chemoreceptor function appears as an essential mediator for these increases in ventilation, since the peripheral chemodenervation has completely abolished the VE response to this particular dose of caffeine.     

Effects of caffeine on social behavior, exploration and locomotor activity: interactions with ethanol

The effects of caffeine and its interaction with ethanol were examined in a test of social behavior and a holeboard test of exploration and locomotion. Male mice were injected i.p. with 15, 30 or 60 mg/kg caffeine alone or in combination with 2 g/kg ethanol. The animals were then put in pairs into a familiar arena, or examined individually in the holeboard. Only the highest dose of caffeine (60 mg/kg) had a significant effect on the time spent in social interaction and motor activity in the social behavior test: both measures were reduced. The duration and frequency of avoidance-irritability behavior was dose-dependently increased by caffeine. In the holeboard, caffeine caused a dose-dependent increase in locomotor activity. 30 mg/kg caffeine reversed the ethanol-induced reduction of time spent in social interaction, and 60 mg/kg caffeine antagonized the ethanol-induced increase in locomotor activity in both the social behavior and holeboard tests. Caffeine's effects on ethanol-induced behavioral changes are compared with those of other drugs.     

Effect of alcohol and kolanut interaction on brain sodium pump activity in Wistar Albino rats.

Effect of alcohol-kolanut interaction on Sodium Pump activity in wistar albino rats was studied. Thirty wistar albino rats were divided into six groups of five (5) rats per group and used for the study. The control group (1) received via oral route a placebo (4ml of distilled water). Groups 2 to 6 were treated for a period of 21 days, with (10% v/v) of alcohol (group 2), 50mg/kg body weight of kolanut (group 3), 50 mg/kg body weight of caffeine (group 4), 4ml of 10% v/v of alcohol and 50 mg/kg body weight kolanut (group 5), 4ml of 10% v/v of alcohol and 50 mg/kg body weight of caffeine in 4.0ml of the vehicle via gastric intubation respectively. A day after the final exposure, the brain of each rat was harvested and processed to examine several biochemical parameters, i.e., total ATpase, ouabain-insensitive ATpase, ouabain sensitive ATpase (Na(+)-K(+)ATPase), non-enzymatic breakdown of ATP and inorganic phosphate (Pi) released. The results showed that the essential enzyme of the brain responsible for neuronal function, Na(+)-K(+)ATPase, was inhibited by alcohol-kolanut co-administration relative to control, resulting in a decrease in Na(+)-K(+)ATPase activity, ATP production, ion transport and action potential, leading to loss of neuronal activities.     

Possible involvement of GABAergic mechanism in protective effect of melatonin against sleep deprivation-induced behavior modification and oxidative damage in mice

Sleep deprivation for 72 h caused anxiety like behavior, weight loss, impaired locomotor activity and oxidative damage as indicated by increase in lipid peroxidation, nitrite level and depletion of reduced glutathione and catalase activity in sleep deprived mice brain. Treatment with melatonin (5 and 10 mg/kg, ip) significantly improved locomotor activity, weight loss and antianxiety effect as compared to control (sleep deprived). Biochemically, melatonin treatment significantly restored depleted reduced glutathione, catalase activity, attenuated lipid peroxidation and nitrite level as compared to control (72 h sleep-deprived) animals. A combination of flumazenil (0.5 mg/kg, ip) and picrotoxin (0.5 mg/kg, ip) with lower dose of melatonin (5 mg/kg, ip) significantly antagonized the protective effect of melatonin. However, combination of muscimol (0.05 mg/kg, ip) with melatonin (5 mg/kg, ip) potentiated protective effect of melatonin as compared to their effect per se. The results suggest that melatonin may produce its protective effect by involving GABAergic system against sleep deprivation-induced anxiety like behavior and related oxidative damage.     

Effects of melatonin on carbon tetrachloride-induced changes in rat serum

Carbon tetrachloride (CCl4) is a volatile organic chemical, which causes tissue damage, especially to the liver and kidney. In experimental animals it has been shown to be carcinogenic. This study was designed to evaluate the effects of exogenous melatonin administration on the CCl4-induced changes of some biochemical parameters in rat blood. Twenty-four male Wistar rats were randomly divided into three equal groups: Control, CCl4 and CCl4 plus melatonin (CCl4+MEL). Rats in CCl4 group were injected subcutaneously with CCl4 0.5 ml/kg in olive oil while rats in CCl4+MEL group were injected with CCl4 (0.5 ml/kg) plus melatonin (25 mg/kg in 10% ethanol) every other day for one month. Control rats were treated with olive oil. Serum urea, creatinine, total protein, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and conjugated bilirubin, alkaline phosphatase (ALP), gamma-glutamyl transferase (gamma-GT), total iron, and magnesium levels were determined. Serum AST, ALT, total and conjugated bilirubin, ALP, gamma-GT, and total iron levels were significantly higher in CCl4-treated rats than in the controls, while urea, total protein, and albumin levels were significantly lower. Melatonin treatment did not cause a significantly change in serum urea, total protein, and albumin levels. However, the elevations in AST, ALT, total and conjugated bilirubin, ALP, gamma-GT, and total iron levels induced by CCl4 injections were significantly reduced by melatonin. On the other hand, melatonin administration significantly decreased serum magnesium levels. These results indicate that melatonin could be a protective agent against the CCl4 toxicity in rats, most likely through its antioxidant and free radical scavenger effects.     

Effect of orally administered l-tryptophan on serotonin,melatonin, and the innate immune response in the rat

To assess the effects of external administration of L-tryptophan on the synthesis of serotonin and melatonin as well as on the immune function of Wistar rats, 300 mg of the amino acid were administered through an oral cannula either during daylight (08:00) or at night (20:00) for 5 days. Brain, plasma, and peritoneal macrophage samples were collected 4 h after the administration. The accumulation of 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition was used to measure the rate of tryptophan hydroxylation in vivo. Circulating melatonin levels were determined by radioimmunoassay, and the phagocytic activity of macrophages was measured by counting, under oil-immersion phase-contrast microscopy, the number of particles ingested. The results showed a diurnal increase (p < 0.05) in the brain 5-HTP, serotonin (5-hydroxytryptamine, 5-HT), and 5-hydroxyindolacetic acid (5-HIAA) of the animals which had received tryptophan at 08:00 and were killed 4 h later. In the animals which received tryptophan during the dark period, the 5-HT declined but the 5-HT/5-HIAA ratio remained unchanged. There was also a significant increase (p < 0.05) in nocturnal circulating melatonin levels and in the innate immune response of the peritoneal macrophages in the animals which had received tryptophan at 20:00. The results indicated that the synthesis of serotonin and melatonin, as well as the innate immune response, can be modulated by oral ingestion of tryptophan.     

Effect of chronic caffeine administration on theophylline concentrations required to produce seizures in rats

Caffeine as well as the antiasthmatic drug theophylline can cause seizures when administered to humans or animals in excessive doses. Studies on rats have shown rapid development of functional tolerance to caffeine-induced seizures whereas repeated pretreatment with theophylline had no significant effect on the theophylline concentrations required to produce seizures. The purpose of this investigation was to determine whether chronic exposure to caffeine can affect susceptibility to the convulsant effect of theophylline. Rats received caffeine, 40 mg/kg, or solvent twice a day for 7 days as an intravenous injection. On the eighth day, theophylline was infused intravenously until the onset of maximal seizures. At this pharmacologic end point, rats pretreated with caffeine had significantly higher theophylline concentrations in the brain and cerebrospinal fluid than did control (solvent-pretreated) animals. Although the concentration differences were relatively small (approximately 11%), they demonstrate in principle the development of caffeine-induced tolerance to the neurotoxic effect of theophylline. Additional experiments showed that the caffeine effect on theophylline neurotoxicity is not acutely mediated by paraxanthine, a major metabolite of caffeine.     

Effects of melatonin in reducing the toxic effects of doxorubicin

Anthracycline antibiotics, such as doxorubicin and daunorubicin, constitute a group of wide spectrum therapeutic agents. Application of these drugs in chemotherapy is limited because of their toxic effects. Melatonin, the main secretory product of pineal gland, was recently found as a free radical scavenger and antioxidant.We decided to evaluate the tissue protective effect of melatonin against toxic effects of doxorubicin in six groups of rats. Rats were given doxorubicin (Dx) (45 mg/kg dose), melatonin (MEL) (10 mg/kg), first doxorubicin and then melatonin (DM), first melatonin and then doxorubicin (MD).The degree of kidney, lung, liver and brain cells' alterations were examined biochemically.In doxorubicin-treated group, malondialdehyde (MDA) levels of kidney, lung, liver and brain tissues were significantly increased but glutathione (GSH) levels were decreased compared to control rats. In the group in which first doxorubicin and then melatonin were given, MDA levels were significantly decreased compared to the doxorubicin-treated group.In doxorubicin-treated group, serum levels of creatinine, uric acid, blood urea nitrogen (BUN), Gamma-glutamyl transpeptidase (GGT) and Lactic acid dehydrogenase (LDH) were significantly increased while serum albumin and total protein levels were significantly decreased compared to control rats.Melatonin decreased the intensity of the changes produced by the administration of doxorubicin alone. Melatonin was quite efficient in reducing the formation of lipid peroxidation, restoring the tissue GSH contents and alterations of serum levels.     

Effect of a divided caffeine dose on endurance cycling performance, postexercise urinary caffeine concentration, and plasma paraxanthine.

This study compared the effects of a single and divided dose of caffeine on endurance performance and on postexercise urinary caffeine and plasma paraxanthine concentrations. Nine male cyclists and triathletes cycled for 90 min at 68% of maximal oxygen uptake, followed by a self-paced time trial (work equivalent to 80% of maximal oxygen uptake workload over 30 min) with three randomized, balanced, and double-blind interventions: 1) placebo 60 min before and 45 min into exercise (PP); 2) single caffeine dose (6 mg/kg) 60 min before exercise and placebo 45 min into exercise (CP); and 3) divided caffeine dose (3 mg/kg) 60 min before and 45 min into exercise (CC). Time trial performance was unchanged with caffeine ingestion (P = 0.08), but it tended to be faster in the caffeine trials (CP: 24.2 min and CC: 23.4 min) compared with placebo (PP: 28.3 min). Postexercise urinary caffeine concentration was significantly lower in CC (3.8 micro g/ml) compared with CP (6.8 micro g/ml). Plasma paraxanthine increased in a dose-dependent fashion and did not peak during exercise. In conclusion, dividing a caffeine dose provides no ergogenic effect over a bolus dose but reduces postexercise urinary concentration.     

Rat blood and brain amino acid pattern in short term experimental diabetes

Some serum and brain amino acid variations occurring in animals with short term streptozotocin-diabetes (24 h) are studied in this work. Diabetic animals showed an increase in serum of the three branched-chain amino acids as well as an increase in free tryptophan, besides a decrease in total serum tryptophan and in the tryptophan/competitor amino acids ratio. In brain, the three branched-chain amino acids increased, but there were no variation in whole brain tryptophan. Nevertheless, by studying levels of tryptophan in different brain regions, an increase in medulla-pons was recorded. This circumstance could be explained by the increase in free serum tryptophan levels, in agreement with several authors who assign this reason for brain tryptophan.     

Liquid chromatographic determination of caffeine in biologic fluids

A high-performance liquid chromatographic procedure was developed for the determination of caffeine in various biologic fluids and coffee. A reversed-phase column and UV detection at 254 nm were used to obtain a sensitivity of 0.1 μg/ml caffeine in serum and saliva using a sample volume of 0.1 ml. Caffeine metabolites and commonly ingested xanthines do not interfere with the assay. The within-day coefficients of variation were 9.8 and 9.9% at plasma caffeine concentrations of 2 and 10 μg/ml, respectively. The day-to-day coefficients of variation were 6.8 and 6.6% at plasma caffeine concentrations of 2 and 10 μg/ml, respectively. Serum and saliva caffeine concentrations were determined following a single oral dose of coffee and an intravenous infusion of caffeine in one subject. Computer estimates of caffeine pharmacokinetic parameters in one subject are in excellent agreement with previously published values.     

Rapid repletion of brain serotonin in malnourished corn-fed rats following L-tryptophan injection.

The concentration of tryptophan in serum, and the levels of tryptophan, serotonin (5-HT), and 5-hydroxyindole-acetic acid (5-HIAA) in brain are substantially reduced in rats that consume for 6 weeks a diet in which corn is the only source of protein. Single injections of L-tryptophan (25, 50, or 100 mg/kg) cause dose-related increases in brain tryptophan, 5-HT, and 5-HIAA in corn-fed animals. At each dose, brain tryptophan content rises to a proportionately greater extent in corn-fed rats than in well-nourished controls, even though serum tryptophan concentrations attain higher levels in controls. This difference may reflect the greatly reduced serum concentrations in corn-fed rats of other large neutral amino acids that compete with tryptophan for uptake into the brain (tyrosine, phenylalanine, leucine, isoleucine, and valine). However, the substantial decrease in serum albumin levels also diminishes the binding of tryptophan to serum albumin; thus it is not yet possible to state which of these changes is responsible for the much greater increments in brain tryptophan observed in corn-fed rats after tryptophan injection. The fact that tryptophan administration rapidly restores brain 5-hydroxyindole levels in corn-fed animals suggests that the reductions in 5-HT and 5-HIAA levels associated with this type of malnutrition may be largely caused by inadequate availability of substrate.     

Effect of different protocols of caffeine intake on metabolism and endurance performance.

Competitive athletes completed two studies of 2-h steady-state (SS) cycling at 70% peak O(2) uptake followed by 7 kJ/kg time trial (TT) with carbohydrate (CHO) intake before (2 g/kg) and during (6% CHO drink) exercise. In Study A, 12 subjects received either 6 mg/kg caffeine 1 h preexercise (Precaf), 6 x 1 mg/kg caffeine every 20 min throughout SS (Durcaf), 2 x 5 ml/kg Coca-Cola between 100 and 120 min SS and during TT (Coke), or placebo. Improvements in TT were as follows: Precaf, 3.4% (0.2-6.5%, 95% confidence interval); Durcaf, 3.1% (-0.1-6.5%); and Coke, 3.1% (-0.2-6.2%). In Study B, eight subjects received 3 x 5 ml/kg of different cola drinks during the last 40 min of SS and TT: decaffeinated, 6% CHO (control); caffeinated, 6% CHO; decaffeinated, 11% CHO; and caffeinated, 11% CHO (Coke). Coke enhanced TT by 3.3% (0.8-5.9%), with all trials showing 2.2% TT enhancement (0.5-3.8%; P < 0.05) due to caffeine. Overall, 1) 6 mg/kg caffeine enhanced TT performance independent of timing of intake and 2) replacing sports drink with Coca-Cola during the latter stages of exercise was equally effective in enhancing endurance performance, primarily due to low intake of caffeine (approximately 1.5 mg/kg).     

Inhibition of anticonvulsant action of carbamazepine by aminophylline and caffeine in rats

Interaction of two well known methyl xanthines, aminophylline--an antiasthmatic agent--and caffeine--commonly present in beverages, on the seizure protective ability of carbamazepine (CBZ) against electrically and chemically induced seizures in rats was investigated. Aminophylline (75 mg/kg, ip) did not alter the activity of CBZ (10 mg/kg, ip; ED100) on maximal electroshock seizures while dose dependent antagonism of CBZ efficacy was seen at 100 and 150 mg/kg, ip. Similar effects were observed with caffeine (200 and 250 mg/kg, ip). At the highest tolerated doses, aminophylline (150 mg/kg, ip) and caffeine (250 mg/kg, ip) produced antagonism of CBZ protection against pentylenetetrazole seizures. These observations support the possibility that the antagonism due to the interaction of these drugs could be related to their action at adenosine receptor sites in the brain.     

Effect of caffeine on peripheral chemoreceptor activity in premature neonates: interaction with sleep stages.

Caffeine is widely used for the treatment of apnea in premature neonates. However, the localization of caffeine's target site (central nervous system and/or peripheral chemoreceptors) is not well defined, especially for sleeping neonates whose sleep stages interact with respiratory control. The aim of this study was to assess the activity of the peripheral chemoreceptors in relation to sleep stages in premature neonates treated (or not) with caffeine for idiopathic apnea. Peripheral chemoreceptor activity was assessed in 22 neonates (postconceptional age of 36 +/- 1 wk with birth weights ranging from 790 to 1,910 g) by performing a 30-s hyperoxic test during active and quiet sleep. Eleven neonates received caffeine treatment (4.0 +/- 0.5 mg.kg(-1).day(-1)) and 11 served as controls. For all neonates, the decrease in minute ventilation observed during hyperoxia was greater during active than during quiet sleep. Neonates receiving caffeine showed a significantly greater decrease in ventilation during hyperoxia in both sleep stages, compared with controls (caffeine; -29.7 +/- 12.8% vs. control; -22.0 +/- 7.4%; F(1,15) = 4.6, P = 0.04). We conclude that caffeine administration increases the effectiveness of chemoreceptor activity. Because sleep stage durations were not affected by the treatment, it is likely that the decrease in apneic episodes typically observed with caffeine therapy is only related to respiratory processes and is independent of the sleep stage organization.     

Minimal effect of acute caffeine ingestion on intense resistance training performance

The primary aim of the study was to determine the efficacy of acute caffeine intake to enhance intense resistance training performance. Fourteen resistance-trained men (age and body mass = 23.1 ± 1.1 years and 83.4 ± 13.2 kg, respectively) who regularly consumed caffeine ingested caffeine (6 mg · kg(-1)) or placebo 1 hour before completion of 4 sets of barbell bench press, leg press, bilateral row, and barbell shoulder press to fatigue at 70-80% 1-repetition maximum. Two minutes of rest was allotted between sets. Saliva samples were obtained to assess caffeine concentration. The number of repetitions completed per set and total weight lifted were recorded as indices of performance. Two-way analysis of variance with repeated measures was used to examine differences in performance across treatment and sets. Compared to placebo, there was a small but significant effect (p < 0.05) of acute caffeine intake on repetitions completed for the leg press but not for upper-body exercise (p > 0.05). Total weight lifted across sets was similar (p > 0.05) with caffeine (22,409.5 ± 3,773.2 kg) vs. placebo (21,185.7 ± 4,655.4 kg), yet there were 9 'responders' to caffeine, represented by a meaningful increase in total weight lifted with caffeine vs. placebo. Any ergogenic effect of caffeine on performance of fatiguing, total-body resistance training appears to be of limited practical significance. Additional research is merited to elucidate interindividual differences in caffeine-mediated improvements in performance.