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At least 19 recordsLinked to original sources
PubMed2000

Caffeine as a model drug of dependence: recent developments in understanding caffeine withdrawal, the caffeine dependence syndrome, and caffeine negative reinforcement.

Caffeine is an excellent model compound for understanding drugs of abuse/dependence. The results of self-administration and choice studies in humans clearly demonstrate the reinforcing effects of low and moderate doses of caffeine. Caffeine reinforcement has been demonstrated in about 45% of normal subjects with histories of moderate and heavy caffeine use. Recent studies provide compelling evidence that caffeine physical dependence potentiates the reinforcing effects of caffeine through the mechanism of withdrawal symptom avoidance. Tolerance to the subjective and sleep-disrupting effects of caffeine in humans has been demonstrated. Physical dependence as reflected in a withdrawal syndrome in humans has been repeatedly demonstrated in adults and recently demonstrated in children. Withdrawal severity is an increasing function of caffeine maintenance dose, with withdrawal occurring at doses as low as 100 mg per day. Increased cerebral blood flow may be the physiological mechanism for caffeine withdrawal headache. Case studies in adults and adolescents clearly demonstrate that some individuals meet DSM-IV diagnostic criteria for a substance dependence syndrome on caffeine, including feeling compelled to continue caffeine use despite desires and recommendations to the contrary. Survey data suggest that 9% to 30% percent of caffeine consumers may be caffeine dependent according to DSM-IV criteria.

Adolescent↗
PubMed1991

The caffeine contracture test for malignant hyperthermia: caffeine citrate, caffeine benzoate or caffeine free base?

The aim of the present study was to investigate whether the three different caffeine preparations--caffeine citrate, caffeine benzoate and the free base--used for in vitro diagnosis of malignant hyperthermia susceptibility--produced the same amount of contracture in rat diaphragm. At equimolar caffeine concentrations, the pure base generated more tension in the rat diaphragm muscle than caffeine benzoate or caffeine citrate. The citrate lowers the pH and the free Ca2+ concentration of the test bath and thus suppresses the caffeine contracture. The benzoate is believed to inhibit the caffeine contracture by its carbonyl group in a way similar to the effect of benzocaine.

Animals↗
PubMed1990

Caffeine consumption, expectancies of caffeine-enhanced performance, and caffeinism symptoms among university students.

The expectancies paradigm developed in alcohol research was used to study caffeine consumption and signs of caffeinism in two groups of college students. A survey questionnaire was developed to gather self-report data on expectations of caffeine-enhanced performance (EP-CAFF), level of beverage caffeine consumed daily, and DSM-111 caffeinism signs reportedly experienced after consumption of caffeinated beverages. A positive association between EP-CAFF and both caffeine consumption and caffeinism signs was predicted. In both initial (n = 527) and cross-validation (n = 270) samples, significant correlations between EP-CAFF scores and both caffeine consumption and caffeinism symptoms were found. A small, but statistically significant, relationship was also found between caffeinism symptoms and both alcohol consumption and cigarette smoking. Of the 797 subjects in the combined sample, 151 (18.9%) endorsed five or more DSM-III caffeinism signs. Subjects endorsing five or more signs of caffeinism scored higher on the EP-CAFF scale, and consumed more caffeine and alcohol in both studies and smoked more cigarettes in study one--but not in study two--than did subjects who endorsed fewer than five caffeinism signs. Results support the utility of extending the expectancies model of substance use motivation from alcohol to caffeine.

Alcohol Drinking↗
PubMed2003

Caffeine reinforces flavour preference in caffeine-dependent, but not long-term withdrawn, caffeine consumers.

RATIONALE: Previous studies have shown that caffeine can reinforce flavour liking in overnight deprived moderate caffeine consumers (e.g. average of 250 mg/day) but not in low consumers (<120 mg/day). However, it is not possible to determine whether the difference between moderate and low caffeine consumers results from pre-existing individual differences in response to caffeine, or results directly from the different amounts of caffeine they habitually consume. If the former were true, then moderate consumers who are completely withdrawn should still manifest the flavour conditioning effect. Conversely, if the latter were true, consumers who are completely withdrawn should not manifest the effect. OBJECTIVES: To examine whether moderate caffeine consumers who have been fully withdrawn from caffeine manifest the flavour conditioning effect. METHODS: In a double-blind study, 48 moderate caffeine consumers refrained from consuming caffeine for 4 weeks and were given replacement drinks to consume, which were either caffeinated (maintained group) or decaffeinated (withdrawn group). In the final 2 weeks, all subjects evaluated a novel drink containing either 100 mg caffeine or placebo on four non-consecutive days. RESULTS. The rated pleasantness of the novel drink containing caffeine increased over the four test days in the group maintained on caffeine, but pleasantness of the same drink fell significantly in the withdrawn group. CONCLUSIONS: These data suggest that the ability of caffeine to reinforce changes in flavour liking are driven by the alleviation of withdrawal symptoms among habitual caffeine consumers and provide further support for the negative reinforcement theory.

Adult↗
PubMed2001

Effects of caffeine, caffeine-associated stimuli, and caffeine-related information on physiological and psychological arousal.

RATIONALE: To test the classical conditioning and expectancy theories of placebo effects. OBJECTIVE: Two experiments investigated whether administration of caffeine-associated stimuli elicited conditioned arousal, and whether information that a drink contained or did not contain caffeine modulated arousal. METHOD: Experiment 1 (n=21) used a 2 Caffeine (0 and 2 mg/kg) x 2 Solution (Coffee, Juice) x 2 Information (Told caffeine, Told not-caffeine) within-subjects design. Experiment 2 (n=48) used a 2 Solution (Coffee, Orange juice) x 3 Information (Told caffeine, Told not-caffeine, No information) between-subjects design. Indexes of arousal were skin conductance responses and levels, startle eyeblink reflexes, cardiovascular measures, and the Bond and Lader 1974 mood scale. RESULTS: Caffeine-associated stimuli increased alertness, contentedness and skin conductance levels, and information that the drink contained caffeine decreased calmness in Experiment 1. However, unexpected information about the caffeine content of the drink, and the order of the conditions, could have masked some effects of the experimental manipulations. Experiment 2 followed up this hypothesis. The results showed a conditioned increase in startle eyeblink reflexes, and that caffeine-associated stimuli together with information that the drink contained caffeine increased contentedness. CONCLUSIONS: Caffeine-associated stimuli increased arousal, and information about the content of the drink modulated arousal in the direction indicated by the information. Thus, both the classical conditioning and expectancy theories of placebo effects received support, and placebo effects were strongest when both conditioned responses and expectancy-based responses acted in the same direction.

Adult↗
PubMed1991

Caffeine renal clearance and urine caffeine concentrations during steady state dosing. Implications for monitoring caffeine intake during sports events.

1. Relationships between the plasma and urine concentrations and clearances of caffeine over successive dosage intervals at steady-state were investigated in six healthy volunteers administered caffeine, 150 mg 8 hourly for 6 days. 2. There was marked inter-individual variability in the urine (15.9-fold range) and steady-state plasma (8.1-fold range) concentrations of caffeine. 3. Urine caffeine concentrations were similar to those in plasma, with mean ratios (plasma:urine) ranging from 1.10 to 1.74. There was a good correlation (r = 0.93, P less than 0.01) between caffeine urine and plasma concentrations. 4. There was a good correlation between caffeine renal clearance and urine flow rate (r = 0.89, P less than 0.01). Caffeine renal clearance was not significantly different from the product of fu and urine flow rate, where fu is the fraction of caffeine unbound in plasma. Urine caffeine concentration and urine flow rate were not correlated (r = 0.14, P greater than 0.05). 5. The results indicate that caffeine is reabsorbed from the renal tubule to equilibrium with unbound caffeine in plasma. 6. A regulatory urine caffeine concentration limit of 12 mg 1(-1) may be exceeded by some individuals with coffee intake in the range 3 to 6 cups per day.

Adult↗
PubMed1988

Caffeine intake, fasting plasma caffeine and caffeine clearance in patients with liver diseases.

The effects of a variable daily administration of caffeine on fasting levels of caffeine in plasma and in saliva were measured in 24 patients with liver disease and hepatocellular dysfunction of variable degree. For 2 consecutive days the patients received either 250 mg of caffeine (in 2 separate doses of 125 mg each at 8:00 a.m. and at 6:00 p.m.) or a single dose of 125 mg at 6:00 p.m. Caffeine clearance was also measured and the results were correlated with the galactose elimination capacity and with antipyrine clearance. At the beginning of the study, fasting caffeine concentrations were largely variable, without any relation to liver function. A strict negative correlation between fasting caffeine and caffeine clearance was only observed after 2 days of controlled caffeine administration (rs = -0.814). Under these conditions, fasting caffeine also correlated with antipyrine clearance (rs = -0.671, n = 20) and with galactose elimination (rs = -0.565). Our data prove that fasting caffeine concentrations after an evening dose may be used as an index of liver function only in subjects under a strictly controlled dietary caffeine intake. The large availability of caffeine in the diet makes the compound scarcely reliable for a correct measurement of liver function based on a single sample, and correct clearance determination is needed.

Body Weight↗
PubMed1986

Assessment of caffeine exposure: caffeine content of beverages, caffeine intake, and plasma concentrations of methylxanthines.

The caffeine content of all tea or coffee beverages consumed by 17 healthy adults over 24 hours was measured. Plasma caffeine, theophylline, theobromine, and paraxanthine concentrations were determined over the same 24 hours. The average caffeine content per drink was 60.4 +/- 21.8 mg for instant coffee (14-fold range), 80.1 +/- 19.2 mg for brewed coffee (2.8-fold range), and 28.8 +/- 13.7 mg for tea (5.5-fold range). The number of drinks of coffee and tea consumed was a poor index of actual caffeine intake (r2 = 0.42). Caffeine intake correlated poorly with the 24-hour average caffeine concentration (r2 = 0.41), but there was a very good correlation between a single plasma caffeine concentration measured at 5 PM and the 24-hour average concentration (r2 = 0.94). The same was true for paraxanthine (r2 = 0.86). Paraxanthine accounted for 67.3% of the total dimethylxanthines in plasma, while theobromine and theophylline accounted for 24.4% and 8.3%, respectively. Mean caffeine clearance was 1.2 +/- 0.3 ml/min/kg. Plasma caffeine concentration before the first drink in the morning correlated very poorly with caffeine clearance (r2 = 0.07), even when adjusted for caffeine intake (r2 = 0.21).

Adult↗
PubMed1988

Caffeine in sport. Urinary excretion of caffeine in healthy volunteers after intake of common caffeine-containing beverages.

The presence of a concentration of caffeine greater than or equal to 15 micrograms/ml in urine of athletes participating in competitive sport is a disqualifying factor. A study was conducted to establish how much caffeine needs to be ingested--in the form of coffee, tea or Coca-Cola--to approach or exceed this limit. Nine healthy volunteers participated in a randomised cross-over study and received caffeine in the form of these beverages, ingested within 15 minutes, in doses ranging from 1.52 mg/kg to 17.53 mg/kg. The latter dose is equivalent to nearly 8 cups of ordinary percolated coffee. The maximum caffeine concentration in urine recorded was 14 micrograms/ml, 3 hours after ingestion. A significant correlation was found between the caffeine dose and the maximum urinary concentration. The mean recovery of caffeine in urine was between 0.74% and 0.91% of the administered dose. The nature of the beverage did not appear to influence the degree of caffeine excretion. It is concluded that if a concentration of 15 micrograms caffeine/ml urine is recorded, it can safely be accepted that the athlete purposely ingested large amounts of the substance, in whatever form.

Adolescent↗
PubMed1988

Caffeine disposition in the pregnant rabbit. II. Fetal distribution of caffeine and paraxanthine during chronic maternal caffeine administration.

Twenty-three New Zealand White rabbits received a continuous intravenous infusion of caffeine during gestation. The amniotic fluid/maternal plasma concentration ratio was higher for caffeine than for its major metabolite, paraxanthine, throughout gestation, and increased near term for both compounds. Both compounds distributed nearly homogeneously to fluids and tissues of the 29-day fetus, with mean fetal/maternal concentration ratios of 0.7 for paraxanthine and 0.9 for caffeine. The free fraction of caffeine was constant during gestation (about 0.8), while that of paraxanthine increased from 0.25 to 0.4. Similar results were observed in 3 Dutch Belted rabbits given caffeine in their drinking water and sacrificed at 29 days of gestation.

Albumins↗
PubMed1980

On the interaction of caffeine with nucleic acids. III. 1H NMR studies of caffeine--5'-adenosine monophosphate and caffeine-poly(riboadenylate) interactions.

1) The self-association of both caffeine (Cf) and 5'-adenosine monophosphate (AMP) in aqueous solution has been reinvestigated by 1H NMR. The self-association process is characterized by an isodesmic model. The apparent self-association constants of the vertical stacking process are KCf = (10.6 +/- 1.0) M-1 and KAMP = (1.67 +/- 0.17) M-1. The arrangement of the monomeric units in the stacked aggregates is discussed in terms of isoshielding curves theoretically calculated by Giessner-Prettre and Pullman. Models are proposed which are consistent with these and further previous NMR data. 2) The interaction of Cf and AMP has been studied by 1H NMR. The apparent association constant of the complex Cf-AMP is KC-A = (7.3 +/- 1.2) M-1. Two models of the mutual arrangement of AMP and Cf in the complex are proposed on the basis of the calculated isoshielding curves considering both ring current and local atomic diamagnetic anisotropy effects. 3) The interaction of Cf and poly(riboadenylate), (rA)n, is indicated by a downfield shift of the H-8 line but an upfield shifts of the H-2 line in the 1H NMR spectra of (rA)n. The concentration dependence of the 1H NMR shifts of both Cf and (rA)n can be explained by the existence of two binding mechanisms. We suggest (i) partial insertion of Cf between adjacent base residues of ordered single-stranded regions of (rA)n and (ii) outside binding of Cf in form of monomeric Cf as well as of self-associated aggregates. The complex geometry of insertion proposed on the basis of the calculated isoshielding curves is characterized by a stronger overlapping of the Cf ring and the H-2 proton of (rA)n as compared to the H-8 proton.

Adenosine Monophosphate↗
PubMed1988

Interaction of caffeine with acetaminophen in mice: schedule dependency of the antagonism by caffeine of acetaminophen hepatotoxicity and the effects of caffeine metabolites, allopurinol, and diethyl ether.

Administration of caffeine (CAF) to mice as early as 6 hr prior to injection of a hepatotoxic but nonlethal dose of acetaminophen (ACM) significantly antagonized the hepatotoxic action of ACM as judged by serum levels of alanine aminotransferase (ALT) activity. Administration of CAF after ACM produced complete antagonism only when CAF was given no later than 1 hr after ACM. Administration of CAF daily for 3 days prior to injection of ACM enhanced ACM toxicity markedly, but little or no toxicity ensued when CAF-pretreated mice received ACM followed immediately by CAF. The four primary metabolites of CAF, 1,3-dimethylxanthine (theophylline), 3,7-dimethylxanthine (theobromine), 1,7-dimethylxanthine (paraxanthine), and 1,3,7-trimethyluric acid were effective and virtually complete antagonists of ACM-induced hepatotoxicity when given immediately after ACM, as were the secondary metabolites, 1-methylxanthine and 1,3-dimethyluric acid. Allopurinol, which reduces theophylline clearance, increases the rate of oxidative N-demethylation of theophylline to 1-methylxanthine, and inhibits conversion of 1-methylxanthine to 1-methyluric acid, was also a dose-dependent antagonist of ACM-induced hepatotoxicity. The hepatotoxic response of mice to ACM is exaggerated by a brief period of diethyl ether anesthesia; CAF given immediately after ACM to previously anesthetized mice suppressed this response and maintained serum ALT levels at control values. It is suggested that CAF and its primary metabolites compete with ACM for biotransformation by the cytochrome P-450 mixed function oxidase system, thereby reducing the rate of formation of the hepatotoxic ACM metabolite.

Acetaminophen↗
PubMed2000

Caffeine for asthma.

BACKGROUND: Caffeine has a variety of pharmacological effects. It is chemically related to the drug theophylline which is used to treat asthma. Accordingly, interest has been expressed in its potential role as an asthma treatment. A number of studies have explored the effects of caffeine in asthma, this is the first review to systematically examine and summarise the evidence. OBJECTIVES: Caffeine is a weak bronchodilator and it also reduces respiratory muscle fatigue. It has been suggested that caffeine may reduce asthma symptoms. The objective of this review was to assess the effects of caffeine on lung function and identify whether there is a need to control for caffeine consumption prior to lung function testing. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register and the reference lists of articles. We also contacted study authors. SELECTION CRITERIA: Randomised trials of oral caffeine compared to placebo in adults with asthma. DATA COLLECTION AND ANALYSIS: Trial quality assessment and data extraction were done independently by two reviewers. MAIN RESULTS: Six trials involving a total of 55 people were included. The studies were all of cross-over design and of high quality. In comparison with placebo, caffeine appears to improve lung function for up to two hours after consumption. Forced expiratory volume in one minute showed a small improvement up to two hours after caffeine use (standardised mean difference -0.73, 95% confidence interval -1.20 to -0.25). Mid-expiratory flow rates also showed a small improvement with caffeine and this was sustained up to four hours. REVIEWER'S CONCLUSIONS: Caffeine appears to improve airways function modestly in people with asthma for up to four hours. People may need to avoid caffeine for at least four hours prior to lung function testing.

Adult↗
PubMed2002

Effects of caffeine on performance and mood depend on the level of caffeine abstinence.

RATIONALE: Most studies of the effects of caffeine on performance have used regular caffeine consumers who are deprived at test. Thus the reported effects of caffeine could be explained through reversal of caffeine withdrawal. OBJECTIVES: To test how preloading deprived caffeine consumers with 0, 1 or 2 mg/kg caffeine altered the subsequent ability of caffeine to modify mood and performance. METHODS: Thirty moderate caffeine consumers were given a drink containing 0, 1 or 2 mg/kg caffeine at breakfast followed 60 min later by a second drink containing either 0 or 1 mg/kg caffeine. Performance on a measure of sustained attention and mood were measured before and after each drink. RESULTS: Administration of both 1 and 2 mg/kg caffeine at breakfast decreased reaction time and 1 mg/kg caffeine also increased performance accuracy on the sustained attention (RVIP) task relative to placebo. Both breakfast doses of caffeine also improved rated mental alertness. Similarly, 1 mg/kg caffeine administered 60 min after breakfast decreased reaction time and increased rated mental alertness in the group who had not been given caffeine at breakfast. However, this second dose of caffeine had no effect on subsequent performance or mood in the two groups who had received caffeine at breakfast. CONCLUSIONS: Caffeine reliably improved performance on a sustained attention task, and increased rated mental alertness, in moderate caffeine consumers who were tested when caffeine-deprived. However, caffeine had no such effects when consumers were no longer caffeine deprived. These data are consistent with the view that reversal of caffeine withdrawal is a major component of the effects of caffeine on mood and performance.

Adult↗
PubMed1986

The effects of caffeine on caffeine users and non-users.

This work examined the effects of consuming relatively small amounts of caffeine, from 20 to 160 mg, on performance and self-reports of mood in a group of caffeine users. A group of non-caffeine users were studied after ingesting 160 mg of caffeine. At regular intervals after consumption subjects were tested on several behavioral measures and blood samples were taken for caffeine analysis. Results showed caffeine users had higher blood caffeine levels and lower blood pressure at some doses than did non-users. Regular caffeine users showed a tendency toward better performance on a rotary pursuit task than non-caffeine users given a placebo treatment. They also experienced a performance decrement, relative to users given placebo, when blood caffeine levels were relatively high. Caffeine users showed no sign of caffeine withdrawal when compared to non-users before caffeine treatment. Performance of non-users given caffeine was poorer than control performance, and they tended not to report altering effects of caffeine. However, in caffeine users, the ratio of alertness:tension self-ratings tended to roughly track plasma caffeine with the lowest ratios occurring when plasma caffeine peaked after 160 mg dose. Low ratios were also found after 0, 20, and 40 mg caffeine treatments. The ratio was highest after 80 mg caffeine, suggesting that an optimum caffeine dose might exist for peak alertness:tension, with higher or lower doses resulting in a decrease of that ratio. These data suggest that real or expected mood and perhaps performance benefits experienced by caffeine users contribute to the motivation for consumption.

Adult↗
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↗
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↗