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PubMed1990

The role of [Ca2+]i and [Ca2+] sensitization in the caffeine contracture of rat myocytes: measurement of [Ca2+]i and [caffeine]i.

1. Fluorescence measurements have been made in single, isolated rat ventricular myocytes using the Ca2(+)-sensitive indicators Fura-2 and Indo-1. In Fura-2-loaded cells, the application of caffeine (2-20 mM) produced a change of fluorescence indicating an increase of [Ca2+]i which then spontaneously decayed to control levels. These changes of [Ca2+]i were accompanied by a contracture. 2. In contrast, in Indo-1-loaded cells, in addition to the changes of fluorescence expected for the transient increase of [Ca2+]i produced by caffeine, there was a maintained decrease of fluorescence. 3. Measurements in vitro showed that caffeine quenches the fluorescence of Indo-1 (but not of Fura-2) in a [Ca2+]-and wavelength-independent manner. Caffeine therefore had no effect on the ratio of Indo-1 fluorescence measured at two wavelengths. This inhibition by caffeine could be described by an apparent Ki of 4 mM. In the cell the Ki was considerably larger (18 mM). 4. We have separated the Indo-1 fluorescence changes into caffeine- and [Ca2+]i-dependent components. The time course of change of intracellular caffeine was calculated. When [caffeine]o was rapidly increased, [caffeine]i changed with a rate constant of 8 s-1 giving an apparent permeability to caffeine of 2 x 10(-3) cm s-1. 5. This method was used to measure [caffeine]i and [Ca2+]i simultaneously during caffeine-induced contractures. The shape of the caffeine contracture was found to depend on both the speed of application of caffeine and the concentration applied. If caffeine was applied quickly then the contracture developed within 1 s to a maximum level and then relaxed to a lower maintained level. With slower application, there was a more complete relaxation of the initial contraction followed by a slower redevelopment of contraction. 6. Despite the difference in contraction time course, irrespective of the flow rate, [Ca2+]i decayed monotonically. The slow secondary development of contraction has the same time course as the increase of [caffeine]i. The caffeine contracture can be reproduced by a model in which both [Ca2+]i and [caffeine]i affect contraction. 7. The increase of [Ca2+]i is not greatly affected by altering the caffeine concentration from 2.5 to 50 mM. In contrast the maintained level of contraction increases over this range showing that the Ca2(+)-independent effects of caffeine on the myofilaments have a low affinity for caffeine.

Animals↗

PubMed2005

Cognitive and psychomotor performance, mood, and pressor effects of caffeine after 4, 6 and 8 h caffeine abstinence.

RATIONALE: Many studies have found that caffeine consumed after overnight caffeine abstinence improves cognitive performance and mood. Much less is known, however, about the effects of caffeine after shorter periods of caffeine abstinence. OBJECTIVES: The aim of this study was to measure the effects on psychomotor and cognitive performance, mood, hand steadiness, blood pressure and heart rate of caffeine administration after periods of 4, 6, and 8 h of caffeine abstinence. METHODS: Participants (n = 49, 27 female) were moderate to moderate-high caffeine consumers (mean daily intake 370 mg/day). Following overnight caffeine abstinence, a 'pre-dose' of caffeine (1.2 mg/kg) was administered at 9 A.M, 11 A.M or 1 P.M. The participants started a baseline battery of measurements at 4 P.M.: before receiving caffeine (1.2 mg/kg) or placebo at 5 P.M.: They then performed the battery of tests again, starting at 5:30 P.M. This was a double-blind, placebo-controlled, randomised study. RESULTS: Performance and mood measurements confirmed a psychostimulant action of caffeine (versus placebo), but only after 8 h of caffeine abstinence. Caffeine also increased blood pressure after 8-h abstinence, whereas hand steadiness was decreased and perception of task demand was increased by caffeine after 4 h, but not after 6- and 8-h abstinence. CONCLUSIONS: A second cup-of-coffee equivalent dose of caffeine only reliably affected cognitive performance and mood after an 8-h interval between doses, but not after shorter intervals (when caffeine had some adverse effects). These results show that, apart from caffeine consumption soon after waking, the daily pattern of caffeine intake of many typical caffeine consumers is not well explained by the short-term psychostimulant effects of caffeine.

Administration, Oral↗

PubMed2003

Absence of reinforcing, mood and psychomotor performance effects of caffeine in habitual non-consumers of caffeine.

RATIONALE: The extent to which the measured (and felt) psychostimulant effects of caffeine represent a real benefit of caffeine consumption or merely withdrawal reversal is unclear. Results showing positive psychostimulant effects of acute caffeine administration in habitual non-consumers of caffeine would provide evidence for a net benefit of caffeine unconfounded by withdrawal. OBJECTIVES: To compare the mood, alerting, psychomotor and reinforcing effects of caffeine in caffeine non-consumers and acutely (overnight) withdrawn caffeine consumers. METHODS: In experiment 1, these participants consumed two differently flavoured drinks, one containing 100 mg caffeine and the other containing no caffeine. Each drink was consumed on 4 separate days in semi-random order, and self-ratings of mood and alertness were completed before and after drink consumption. On day 9, both drinks contained 50 mg caffeine and drink preference (choice) and intake were assessed. In experiment 2, mood, alertness and performance on a long-duration simple reaction time task were assessed before and after administration of 100 mg or placebo in a single test session. RESULTS: Prior to receiving caffeine, the (overnight withdrawn) caffeine consumers were less alert and more tense than the non-consumers. Caffeine only had significant reinforcing, mood and psychomotor performance effects in the caffeine consumers. The reinforcing effect of caffeine was evident from an effect on drink intake, but drink choice was unaffected. Caffeine increased self-rated alertness of both caffeine consumers and non-consumers; however, for some of the non-consumers this was associated with a worsening of performance. CONCLUSIONS: These results support the hypothesis that the psychostimulant and related effects of caffeine are due largely to withdrawal reversal.

Adolescent↗

PubMed2005

Effects of caffeine and caffeine withdrawal on mood and cognitive performance degraded by sleep restriction.

RATIONALE: It has been suggested that caffeine is most likely to benefit mood and performance when alertness is low. OBJECTIVES: To measure the effects of caffeine on psychomotor and cognitive performance, mood, blood pressure and heart rate in sleep-restricted participants. To do this in a group of participants who had also been previously deprived of caffeine for 3 weeks, thereby potentially removing the confounding effects of acute caffeine withdrawal. METHODS: Participants were moderate to moderate-high caffeine consumers who were provided with either decaffeinated tea and/or coffee for 3 weeks (LTW) or regular tea and/or coffee for 3 weeks (overnight caffeine-withdrawn participants, ONW). Then, following overnight caffeine abstinence, they were tested on a battery of tasks assessing mood, cognitive performance, etc. before and after receiving caffeine (1.2 mg/kg) or on another day after receiving placebo. RESULTS: Final analyses were based on 17 long-term caffeine-withdrawn participants (LTW) and 17 ONW participants whose salivary caffeine levels on each test day confirmed probable compliance with the instructions concerning restrictions on consumption of caffeine-containing drinks. Acute caffeine withdrawal (ONW) had a number of negative effects, including impairment of cognitive performance, increased headache, and reduced alertness and clear-headedness. Caffeine (versus placebo) did not significantly improve cognitive performance in LTW participants, although it prevented further deterioration of performance in ONW participants. Caffeine increased tapping speed (but tended to impair hand steadiness), increased blood pressure, and had some effects on mood in both groups. CONCLUSIONS: The findings provide strong support for the withdrawal reversal hypothesis. In particular, cognitive performance was found to be affected adversely by acute caffeine withdrawal and, even in the context of alertness lowered by sleep restriction, cognitive performance was not improved by caffeine in the absence of these withdrawal effects. Different patterns of effects (or lack of effects) of caffeine and caffeine withdrawal were found for other variables, but overall these results also suggest that there is little benefit to be gained from caffeine consumption.

Adult↗

PubMed2000

Effects of low doses of caffeine on cognitive performance, mood and thirst in low and higher caffeine consumers.

RATIONALE: Caffeine is present in many widely consumed drinks and some foods. In the fairly extensive literature on the psychostimulant effects of caffeine, there are few dose-response studies and even fewer studies of the effects of doses of caffeine lower than 50 mg (the range of the amounts of caffeine contained in, for example, a typical serving of tea or cola). OBJECTIVE: This study measured the effects of 0, 12.5, 25, 50 and 100 mg caffeine on cognitive performance, mood and thirst in adults with low and moderate to high habitual caffeine intakes. METHODS: This was a double-blind, within-subjects study. Following overnight caffeine abstinence, participants (n=23) completed a test battery once before and three times after placebo or caffeine administration. The test battery consisted of two performance tests, a long duration simple reaction time task and a rapid visual information processing task, and a mood questionnaire (including also an item on thirst). RESULTS: Effects on performance and mood confirmed a psychostimulant action of caffeine. All doses of caffeine significantly affected cognitive performance, and the dose-response relationships for these effects were rather flat. The effects on performance were more marked in individuals with a higher level of habitual caffeine intake, whereas caffeine increased thirst only in low caffeine consumers. CONCLUSIONS: After overnight caffeine abstinence, caffeine can significantly affect cognitive performance, mood and thirst at doses within and even lower than the range of amounts of caffeine contained in a single serving of popular caffeine-containing drinks. Regular caffeine consumers appear to show substantial tolerance to the thirst-increasing but not to the performance and mood effects of caffeine.

Adolescent↗

PubMed2005

Attentional bias for caffeine-related stimuli in high but not moderate or non-caffeine consumers.

RATIONALE: Attentional bias for drug-related cues has been reported with a wide range of drugs, but to date the extent to which caffeine consumers show similar biases for caffeine-related stimuli has not been tested. The present study therefore examined this issue in terms of differences in attentional bias for caffeine-related words in High, Moderate and Non-caffeine consumers using a dot-probe word task following overnight caffeine abstinence. OBJECTIVES: This study was conducted to test whether caffeine consumers show an attentional bias for caffeine-related words, and whether such biases relate to habitual levels of caffeine use. METHODS: Sixteen High, Moderate and Non-consumers of caffeine were asked to complete a modified dot-probe task in order to measure attentional bias for caffeine-related relative to neutral control word groups. The task was completed following overnight caffeine abstinence, and participants also completed mood and caffeine-craving measures. RESULTS: The High consumer group showed a significant attentional bias for the caffeine-related words, but no such bias was seen in Moderate or Non-consumer groups. As expected, craving for caffeine was strongest in the High consumers and weakest in the Non-consumers. Attentional bias in the High group correlated with self-reported caffeine consumption and with craving for caffeine, but neither effect was significant in the Moderate group. CONCLUSIONS: These data confirm that High caffeine consumers show attentional bias for caffeine-related stimuli, consistent with current theories of drug addiction.

Adolescent↗

PubMed1996

Validation of urine caffeine metabolite ratios with use of stable isotope-labeled caffeine clearance.

OBJECTIVE: A number of caffeine metabolite ratios have been proposed to measure CYP1A2 activity in vivo. The data to validate these ratios are scanty. The objective of this study was to validate urine caffeine metabolite ratios versus stable isotope-labeled caffeine clearance under different caffeine dosing conditions. STUDY DESIGN: Two experiments, one with nine nonsmoking subjects and the other with 12 cigarette smokers, were performed. We explored the relationship between caffeine clearance, measured by means of intravenous infusions of stable isotope-labeled caffeine, and a number of caffeine metabolite ratios during administration of different single or multiple doses of caffeine to smokers and nonsmokers on three different occasions over a 2-week period, using different durations of urine collections, including spot urines. The stable isotope technique allowed simultaneous oral dosing of caffeine and measurement of caffeine metabolite ratios and caffeine clearance, the latter reflecting CYP1A2 activity. RESULTS: The caffeine metabolite ratio of AAMU + 1U +1X/17U (5-acetylamino-6-amino-3-methyluracil + 1-methyluric acid + 1 methylxanthine/1,7-dimethyluric acid) maintained a significant correlation with caffeine clearance for all the above conditions (gamma2 range, 0.4 to 0.9) except for dose. With high doses of caffeine (12 mg/kg), a significant relationship was not observed. AAMU + 1U + 1X/17U also correlated with the formation clearance of paraxanthine (gamma2 = 0.6, p = 0.002). Other reported caffeine metabolite ratios did not display the same robust correlation with caffeine clearance under all these different conditions. CONCLUSIONS: We conclude that AAMU+1U+1X/17U measured from a single spot urine collection is a valid measure of CYP1A2 activity except at very high levels of caffeine dosing. The validity of the other proposed caffeine metabolite ratios is questionable.

Adult↗

PubMed2005

Caffeine dependence in combination with a family history of alcoholism as a predictor of continued use of caffeine during pregnancy.

OBJECTIVE: The purpose of the study was to examine whether caffeine dependence and a family history of alcoholism are associated with continued use of caffeine during pregnancy. METHOD: Forty-four women seeking obstetrical care in an office-based practice completed questionnaires and provided saliva samples at three prenatal visits occurring 2-3, 3-4, and 7 months postconception. On visit 1, the patients received the physician's instructions to stop using caffeine. Structured interviews were used to assign a diagnosis of caffeine dependence (lifetime) and to identify family history of alcoholism. Outcome measures included self-reported levels of caffeine use and saliva caffeine levels at the three prenatal visits. RESULTS: Although most women eliminated or substantially reduced their caffeine consumption between pregnancy awareness and prenatal visit 1, those with a lifetime diagnosis of caffeine dependence and a family history of alcoholism had higher levels of caffeine use and lower rates of abstinence throughout pregnancy. Saliva caffeine levels confirmed these effects. Withdrawal symptoms, functional impairment, and craving were cited as reasons they failed to eliminate or cut back on caffeine use. Fifty percent of the women with both a lifetime diagnosis of caffeine dependence and a family history of alcoholism continued to use caffeine in amounts (>300 mg/day) greater than those considered safe during pregnancy, compared to none of the women without caffeine dependence and a family history of alcoholism. Women with a lifetime diagnosis of caffeine dependence and a family history of alcoholism also reported higher rates of past cigarette smoking and problematic alcohol use. CONCLUSIONS: Caffeine-dependent women with a family history of alcoholism were not able to follow their physician's advice to reduce or eliminate caffeine consumption during pregnancy, despite their wanting to do so. This subgroup may require more intensive intervention to ensure caffeine abstinence and may be at greater risk for abuse of or dependence on other drugs.

Adult↗

PubMed1985

The effect of caffeine ingestion on pharmacokinetics of caffeine and its metabolites after a single administration in pregnant rats.

The pharmacokinetics of caffeine and its metabolites were studied in pregnant rats in order to clarify the effects of maternal caffeine ingestion on the caffeine disposition. On gestational day 18 the single intravenous or oral 10 mg/kg dose of caffeine was administered to pregnant rats who had received drinking water containing 0.04% caffeine or water ad lib during the premating and/or pregnant periods. Concentrations of caffeine and its dimethylxanthines were simultaneously determined by high-performance liquid chromatography. The caffeine plasma concentration-time curves were analyzed by assumption of a one-compartment model. The apparent volume of distribution of caffeine in rats given caffeine only during pregnancy was decreased. The elimination rate constant (kel) of caffeine in most of the rats taking caffeine during pregnancy was increased. The rats which had received caffeine throughout the premating and pregnant periods had a relatively high total body plasma clearance (CL) of caffeine. The kel and the CL widely varied in the rats taking caffeine during pregnancy. The individual values of kel or CL in pregnant rats were significantly correlated with the molar concentration ratios of the metabolites to caffeine in plasma at 8 h after administration of caffeine. It is concluded that the caffeine disposition is influenced by the different modes of maternal caffeine ingestion during the premating and/or pregnant periods.

Administration, Oral↗

PubMed2005

Cognitive and mood improvements of caffeine in habitual consumers and habitual non-consumers of caffeine.

RATIONALE: The cognitive and mood effects of caffeine are well documented. However, the majority of studies in this area involve caffeine-deprived, habitual caffeine users. It is therefore unclear whether any beneficial findings are due to the positive effects of caffeine or to the alleviation of caffeine withdrawal. OBJECTIVES: The present placebo-controlled, double-blind, balanced crossover study investigated the acute cognitive and mood effects of caffeine in habitual users and habitual non-users of caffeine. METHOD: Following overnight caffeine withdrawal, 24 habitual caffeine consumers (mean=217 mg/day) and 24 habitual non-consumers (20 mg/day) received a 150 ml drink containing either 75 or 150 mg of caffeine or a matching placebo, at intervals of > or =48 h. Cognitive and mood assessments were undertaken at baseline and 30 min post-drink. These included the Cognitive Drug Research computerised test battery, two serial subtraction tasks, a sentence verification task and subjective visual analogue mood scales. RESULTS: There were no baseline differences between the groups' mood or performance. Following caffeine, there were significant improvements in simple reaction time, digit vigilance reaction time, numeric working memory reaction time and sentence verification accuracy, irrespective of group. Self-rated mental fatigue was reduced and ratings of alertness were significantly improved by caffeine independent of group. There were also group effects for rapid visual information processing false alarms and spatial memory accuracy with habitual consumers outperforming non-consumers. There was a single significant interaction of group and treatment effects on jittery ratings. Separate analyses of each groups' responses to caffeine revealed overlapping but differential responses to caffeine. Caffeine tended to benefit consumers' mood more while improving performance more in the non-consumers. CONCLUSIONS: These results do not support a withdrawal alleviation model. Differences in the patterns of responses to caffeine by habitual consumers and habitual non-consumers may go some way to explaining why some individuals become caffeine consumers.

Adolescent↗

PubMed2002

Association of different zinc concentrations combined with a fixed caffeine dose on plasma and tissue caffeine and zinc levels in the rat.

Because caffeine and tissue levels of Zn are closely related, the objectives of this study were to determine the changes in plasma caffeine levels over a period of 5 h when different concentrations of Zn combined with a fixed concentration of caffeine were injected into the femoral vein of rats and to determine the relationship between tissue levels of caffeine and Zn at 5 h postinjection. Rats were divided into three groups: group 1, 220 microg caffeine; group 2, 220 microg caffeine + 8 microg Zn/g body weight (BW); group 3, 220 microg caffeine + 16 microg Zn/g BW. Blood from groups 1 and 3 was collected at 3 min, 30 min, 1 h, 3 h, and 5 h to determine the pharmacokinetics of caffeine. All groups were killed at 5 h. Caffeine and Zn concentrations of the brain, kidney, heart, and liver of all groups were determined. The plasma-caffeine curve in group 3 showed a lower concentration at 3 min and a slower caffeine-elimination rate during the first 3 h. Brain and kidney caffeine levels remained constant in all groups, whereas caffeine levels were increased in the heart in group 2 and in the liver in group 3. Zn concentrations in the brain and kidney were lower in group 2 compared with groups 1 and 3 and higher in group 3 compared to groups 1 and 2. Zn concentration in the heart was the same among the three groups but was increased in the liver in group 3 compared to groups 1 and 2. Therefore, we concluded that caffeine combined with Zn affects caffeine pharmacokinetics. With caffeine intake, levels of Zn (16 microg/g BW) that are slightly higher than the daily requirements (12 microg/g BW) may prevent a reduction of Zn in tissue. In addition, caffeine's effects on Zn concentration among organs are different.

Animals↗

PubMed2000

Effects of caffeine on sensorimotor gating of the startle reflex in normal control subjects: impact of caffeine intake and withdrawal.

RATIONALE: Prepulse inhibition (PPI), a cross-species measure of sensorimotor gating, is impaired in certain neuropsychiatric disorders. This study was designed to assess caffeine effects on PPI in normal humans, as part of an effort to understand cross-species differences and similarities in the neurochemical regulation of PPI. METHODS: Startle was measured during a screening session; 7 days later, subjects were retested after placebo or caffeine (200 mg; double-blind design). Subjects were characterized as low versus high caffeine drinkers based on established scales (range 11-628 mg/day), and either maintained ad libitum caffeine intake (Ad lib study; n=18) or refrained from caffeine consumption for > or =15 h prior to testing (Withdrawal study; n=12). Autonomic and self-rating measures, acoustic and tactile startle, and unimodal and cross-modal PPI, were measured in divided sessions for 3 h post-treatment. RESULTS: There were significant effects of caffeine and/or caffeine withdrawal on several self-rating and autonomic measures, and on startle reflex habituation, but not on acoustic or tactile startle magnitude or PPI. Difference scores of startle data from screening versus test days revealed no group effects on startle magnitude, but PPI difference scores revealed that caffeine had opposite effects on low versus high caffeine drinkers (means=57 versus 258 mg/day) in the two withdrawal states. In the absence of withdrawal, caffeine reduced PPI in heavy caffeine drinkers; during withdrawal, caffeine increased PPI in heavy caffeine drinkers. The opposite pattern was evident in low caffeine drinkers. CONCLUSIONS: While a physiologically active dose of caffeine has no simple effects on PPI in normal humans, both withdrawal states and normal levels of caffeine consumption may be important factors in understanding this drug's effects on sensorimotor gating.

Adolescent↗

PubMed1998

Mood and psychomotor performance effects of the first, but not of subsequent, cup-of-coffee equivalent doses of caffeine consumed after overnight caffeine abstinence.

Moderate caffeine consumers (n = 64, mean caffeine intake 453 mg/day) were deprived of caffeine overnight and semi-randomly allocated to four treatment groups, designated PPP, CPP, CCP and CCC, where P is placebo and C is caffeine (1.2 mg/kg, giving an amount of caffeine similar to that consumed in a serving of ground coffee). Caffeine or placebo (i.e. no caffeine) were administered double-blind in novel fruit juice drinks at 10:15, 11:30 and 13:00 h on the test day. Before (baseline), and 45 min after each of these times the participants completed a mood questionnaire and begun psychomotor performance tests lasting 25 min (1-min tapping task, and a long-duration simple reaction time task (SRT). Caffeine significantly increased energetic mood and improved psychomotor performance relative to placebo. Caffeine had particularly marked effects on SRT performance, ameliorating the slowing of performance with time on task and removing the post-lunch dip in performance. However, the three caffeine treatments, CPP, CCP and CCC, were equally effective. That is, mood and performance were improved to the same extent by one, two and three spaced doses (totalling 86, 172 and 258 mg) of caffeine. This result is consistent with previous findings indicating a flat dose-response relationship for the psychoactive effects of caffeine; and because of the adverse effects (e.g. fatigue) associated with overnight caffeine deprivation, it suggests that there is little net benefit to be gained from frequent caffeine use. At the very least, it appears that the psychostimulant effects of caffeine cannot on their own account for the typical pattern of consumption of caffeine-containing drinks.

Adolescent↗

PubMed2006

Sensitization to caffeine and cross-sensitization to amphetamine: influence of individual response to caffeine.

The present study evaluated the ability of a subchronic intermittent administration of caffeine to induce a sensitized motor response and correlated the individual susceptibility of rats to acute caffeine to the development of sensitization. Moreover, individual susceptibility to caffeine and development of motor behaviour sensitization were correlated to the behavioural response obtained after a challenge with amphetamine. To this end, rats were subdivided in "low" and "high" responders according to their individual susceptibility to acute caffeine established on the basis of the motor activity observed after the first caffeine administration. "Low" and "high" responder rats were then repeatedly and intermittently treated with caffeine (15 mg/kg, i.p.), or vehicle, every other day for fourteen days. Three days after treatment discontinuation, behavioural activation induced by acute amphetamine (0.5 mg/kg, s.c.) was measured in vehicle- and caffeine-pretreated rats. Subchronic caffeine resulted in motor sensitization of a variable degree among rats and no difference were observed between "low" and "high" responders. Moreover, caffeine pretreatment potentiated the behavioural effects of amphetamine according to the degree of caffeine sensitization but not to individual susceptibility to acute caffeine. These results demonstrate that individual susceptibility to acute caffeine does not influence the modifications in caffeine motor effects produced by its subchronic administration and does not affect the enhancement of acute behavioural effects of amphetamine in caffeine-pretreated rats, rather sensitization to subchronic caffeine administration critically influences the behavioural effects of amphetamine.

Amphetamine↗

PubMed1996

Relation of caffeine intake and blood caffeine concentrations during pregnancy to fetal growth: prospective population based study.

OBJECTIVES: To examine the association of plasma caffeine concentrations during pregnancy with fetal growth and to compare this with relations with reported caffeine intake. DESIGN: Prospective population based study. SETTING: District general hospital, inner London. SUBJECTS: Women booking for delivery between 1982 and 1984. Stored plasma was available for 1,500 women who had provided a blood sample on at least one occasion and for 640 women who had provided a sample on all three occasions (at booking, 28 weeks, and 36 weeks). MAIN OUTCOME MEASURE: Birth weight adjusted for gestational age, maternal height, parity, and sex of infant. The exposures of interest were reported caffeine consumption and blood caffeine concentration. Cigarette smoking was assessed by blood cotinine concentration. RESULTS: Caffeine intake showed no changes during pregnancy, but blood caffeine concentrations rose by 75%. Although caffeine intake increased steadily with increasing cotinine concentration above 15 ng/ml, blood caffeine concentrations fell. Caffeine consumption was inversely related to adjusted birth weight, the estimated effect being a 1.3% fall in birth weight for a 1,000 mg per week increase in intake (95% confidence interval 0.5% to 2.1%). The apparent caffeine effect was confined to cigarette smokers, among whom the estimated effect was-1.6%/1000 mg a week (-2.9% to -0.2%) after adjustment for cotinine and -1.3% (-2.7% to 0.1%) after further adjustment for social class and alcohol intake. Adjusted birth weight was unrelated to blood caffeine concentrations overall (P = 0.09, but a positive coefficient), after adjustment for cotinine (P = 0.73), or among current smokers (P = 0.45). CONCLUSIONS: Smokers consume more caffeine than non-smokers. Blood caffeine concentrations during pregnancy are not related to fetal growth, but caffeine intake is negatively associated with birth weight, with this effect being apparent only in smokers. The effect remains of borderline significance after adjustment for other factors. Prudent advice for pregnant women would be to reduce caffeine intake in conjunction with stopping smoking.

Beverages↗

PubMed1995

Overnight caffeine abstinence and negative reinforcement of preference for caffeine-containing drinks.

It has been suggested that liking for the taste, flavour and aroma of, for example, coffee and tea is acquired through the process of classical conditioning, involving association of these orosensory cues with the psychopharmacological consequences of caffeine ingestion. Accordingly, this study investigated caffeine reinforcement by assessing changes in preference for a novel drink consumed with or without caffeine. Particular care was taken to use "ecologically valid" procedures; that is, overnight caffeine abstinence followed by a cup-of-coffee equivalent dose of caffeine (70 mg) at breakfast. Caffeine had no significant effects on drink preference or mood in subjects with habitually low intakes of caffeine. In contrast, moderate users of caffeine developed a relative dislike for the drink lacking caffeine and showed somewhat lowered mood following overnight caffeine abstinence (e.g., less lively, clearheaded and cheerful), which was significantly improved by caffeine. These together with other recent results strongly suggest that, in everyday life, caffeine reinforcement can occur as the result of the alleviation by caffeine of the adverse effects of overnight caffeine abstinence (negative reinforcement). They also demonstrate the utility of this flavour-conditioning procedure, which could be applied in the wider investigation of the reinforcing properties of drugs.

Adolescent↗

PubMed1993

Interaction of caffeine with acetaminophen. 1. Correlation of the effect of caffeine on acetaminophen hepatotoxicity and acetaminophen bioactivation following treatment of mice with various cytochrome P450 inducing agents.

The combination of caffeine with acetaminophen (APAP) is used widely in the treatment of headache. The effects of caffeine on APAP-induced hepatotoxicity and APAP bioactivation by liver microsomes from uninduced mice and from mice pretreated with various agents that induce cytochrome P450 were studied. When 1 mM caffeine was included, the rate of glutathione-APAP conjugate (GS-APAP) formation was increased significantly by 33 and 39% in microsomes from phenobarbital (PB)- and dexamethasone (DEX)-treated mice, respectively, whereas this parameter was decreased 39 and 12% by caffeine in microsomes from beta-naphthoflavone (beta NF)- and acetone-treated mice, respectively. A 5 mM concentration of caffeine increased GS-APAP formation by 47, 107 and 117% in microsomes from control, PB-, and DEX-treated mice, respectively, and decreased it 39 and 25% in microsomes from beta NF- and acetone-treated mice, respectively. Caffeine was a competitive inhibitor of APAP bioactivation in microsomes from beta NF- and acetone-treated mice. While caffeine increased APAP bioactivation in microsomes from uninduced, PB-, and DEX-treated mice, the apparent Km values for APAP were increased by caffeine, indicating that this enhancement was not due to a direct effect of caffeine on APAP binding to cytochrome P450 but may be due to an effect of caffeine on the substrate-enzyme complex. The variable effect of caffeine on APAP hepatotoxicity correlated with the effect of caffeine on APAP bioactivation by liver microsomes, regardless of pretreatment. Lack of correlation of aminopyrine N-demethylase, but good correlation of erythromycin N-demethylase activity with the extent of caffeine enhancement of APAP bioactivation following PB or DEX treatment suggests that a murine P450 subfamily similar to the rat P450 3A subfamily may be the candidate in mediating the stimulatory effect of caffeine on APAP bioactivation and APAP-induced hepatotoxicity.

Acetaminophen↗

PubMed2006

Caffeine and caffeine sodium benzoate have a sunscreen effect, enhance UVB-induced apoptosis, and inhibit UVB-induced skin carcinogenesis in SKH-1 mice.

Topical application of caffeine sodium benzoate (caffeine-SB) immediately after UVB irradiation of SKH-1 mice enhanced UVB-induced apoptosis by a 2- to 3-fold greater extent than occurred after the topical application of an equimolar amount of caffeine. Although topical application of caffeine-SB or caffeine enhanced UVB-induced apoptosis, both substances were inactive on non-UVB-treated normal skin. Topical application of caffeine-SB or caffeine (each has UVB absorption properties) 0.5 h before irradiation with a high dose of UVB decreased UVB-induced thymine dimer formation and sunburn lesions (sunscreen effect). Caffeine-SB was more active than an equimolar amount of caffeine in exerting a sunscreen effect. In additional studies, caffeine-SB strongly inhibited the formation of tumors in UVB-pretreated 'high-risk mice' and in tumor-bearing mice, and the growth of UVB-induced tumors was also inhibited. Caffeine-SB and caffeine are the first examples of compounds that have both a sunscreen effect and enhance UVB-induced apoptosis. Our studies suggest that caffeine-SB and caffeine may be good agents for inhibiting the formation of sunlight-induced skin cancer.

Administration, Topical↗