Caffeine
INTRODUCTION
Caffeine is the most widely used
psychoactive substance and has been considered by some investigators as a
drug of abuse. This article summarizes the available data on caffeine
dependence, tolerance, reinforcement, and withdrawal. After sudden
caffeine cessation, withdrawal symptoms develop in a small portion of the
population, but these symptoms are moderate and transient.
Tolerance to caffeine-induced stimulation of locomotor activity has been shown in animals. In humans, tolerance to some subjective effects of caffeine may occur, but most of the time complete tolerance to many effects of caffeine on the central nervous system (CNS) does not occur. In animals, caffeine can act as a reinforcer but only in a more limited range of conditions than do classic drugs of dependence. In humans, the reinforcing stimulus functions of caffeine are limited to low or moderate doses, while high doses usually are avoided.
Classic drugs of abuse lead to specific increases in cerebral functional activity and dopamine release in the shell of the nucleus accumbens (the key neural structure for reward, motivation, and addiction). In contrast, caffeine at doses reflecting daily human consumption does not induce a release of dopamine in the shell of the nucleus accumbens but leads to a release of dopamine in the prefrontal cortex, which is consistent with its reinforcing properties.
Furthermore, caffeine increases glucose utilization in the shell of the nucleus accumbens only at high concentrations, which, in turn, nonspecifically stimulates most brain structures and thus likely reflects the side effects linked to high caffeine ingestion alone. Also, this dose is 5-10 times higher than the dose necessary to stimulate the caudate nucleus (extrapyramidal motor system) and the neural structures regulating the sleep-wake cycle, the 2 functions that are most sensitive to caffeine. Thus, although caffeine fulfills some of the criteria for drug dependence and shares with amphetamine and cocaine a certain specificity of action on the cerebral dopaminergic system, this methylxanthine does not act on the dopaminergic structures related to reward, motivation, and addiction.
Significant dietary sources of caffeine include coffee, tea, cola drinks, and chocolate. The most notable behavioral effects of caffeine occur after consumption of low to moderate doses (50-300 mg) and include increased alertness, energy, and ability to concentrate. Moderate caffeine consumption rarely leads to health risks. In contrast, higher doses of caffeine induce negative effects such as anxiety, restlessness, insomnia, and tachycardia. These effects are seen primarily in a small group of individuals who are caffeine sensitive. On the other hand, caffeine was considered in one study as a potential drug of abuse and more recently was described as a model drug of abuse. On the basis of a review of science and clinical data, the possibility of adding caffeine withdrawal, but not abuse and dependence, to diagnostic manuals is being considered in the United States.
History
Caffeine was used mainly in the Arab world until the 15th century. It reached Europe during the 16th century, and its consumption spread rapidly. According to recent surveys, coffee consumption varies among countries. Consumption (more than 10 kg/person/year) is highest in Scandinavian countries (as well as in Austria and the Netherlands). In most Western European countries (as well as in Brazil and Costa Rica), coffee consumption ranges from 6-9 kg/person/year. The lowest consumption (less than 5 kg/person/year) occurs in the United States, Italy, Algeria, Nicaragua, and Paraguay. World coffee consumption is increasing.
The average consumption of coffee in 1990 was 1.41 cups per day in Japan, 1.73 cups per day in the United States, and 3.87 cups per day in Germany. In the United States, coffee consumption decreased in 1986 and has not changed significantly since then. In Japan, coffee consumption has been increasing constantly over the last 10 years, while in Germany consumption has been stable over the same period.
The results of a French survey indicate that 4 attitudes are linked positively to the quantity of coffee consumed. In decreasing order of importance they are (1) the need for a stimulant, (2) the preference for strong coffee, (3) the knowledge of coffee, and (4) the preference for the coffee roasting shop. The content of caffeine per cup of coffee varies and is dependent on the size of the serving, the mode of coffee preparation (eg, boiled, filter, percolated, espresso, instant), and the type of coffee used (eg, Arabica, Robusta). The size of a cup of coffee can range from 50-190 mL, and the standard caffeine content in a cup of coffee can be as low as 19 mg/cup for instant coffee and as high as 177 mg/cup in boiled coffee. The content of caffeine in a cup of coffee ranges from 0.7-1.1 mg/mL for boiled or filter coffee, 0.6-3.3 mg/mL for espresso, and 0.2-0.6 mg/mL (but can be as high as 1.0 mg/mL) for instant coffee.
Coffee types
The 2 major coffee types are Arabica and Robusta.
In a standard 150 mL cup, the content of caffeine ranges from 71-120 mg per cup for Arabica coffee and from 131-220 mg per cup for Robusta.
Caffeine consumption
Caffeine is present in a number of dietary sources including tea, coffee, cocoa beverages, candy bars, and soft drinks. The caffeine content of these food items varies, ranging from 71-220 mg/150 mL for coffee, 32-42 mg/150 mL for tea, 32-70 mg/330 mL for cola, and 4 mg/150 mL for cocoa. Average caffeine consumption from all sources is approximately 76 mg/person/day but reaches 210-238 mg/person/day in the United States and Canada and more than 400 mg/person/day in Sweden and Finland, where 80-100% of the caffeine intake is from coffee alone. In the United Kingdom, the consumption of caffeine is similar to that in Sweden and Finland, but 72% is from tea.
The daily intake of caffeine from all sources in the United States is estimated at 3 mg/kg/person, with two thirds of it coming from coffee consumed by subjects older than 10 years. If only caffeine consumers are evaluated, the daily caffeine consumption is 2.4-4.0 mg/kg (170-300 mg) in individuals weighing 60-70 kg. In children, soft drinks represent 55%, chocolate foods and beverages represent 35-40%, and tea represents 6-10% of the total caffeine intake.
PHARMACOLOGY OF CAFFEINEThe metabolism of methylxanthines also is influenced by the presence of other agents or specific diseases. For example, cigarette smoking and oral contraceptives produce a small but appreciable increase in methylxanthine clearance. The half-life of theophylline can be prolonged significantly in patients with hepatic cirrhosis, congestive heart failure, or acute pulmonary congestion; values of more than 60 hours have been reported.
Caffeine has a half-life in plasma of 3-7 hours; this increases by about 2-fold in women during the later stages of pregnancy or with long-term use of oral contraceptive steroids. In premature infants, the rate of elimination of methylxanthines is quite slow.
The ability of methylxanthines to inhibit cyclic nucleotide phosphodiesterases often is cited to explain their therapeutic effects; however, strong evidence for this theory is lacking. Plasma caffeine concentrations that raise blood pressure are below the threshold for phosphodiesterase inhibition. Thus, phosphodiesterase inhibition is probably not important to the therapeutic effects of methylxanthines.
At high concentrations (0.5-1 mmol), caffeine interferes with the uptake and storage of calcium by the sarcoplasmic reticulum in striated muscles. This action can account for observations that such concentrations of caffeine increase the strength and duration of contractions in both skeletal and cardiac muscles. Similar actions can enhance secretion in certain tissues. However, their having an important role at therapeutic concentrations is unlikely. In vitro, methylxanthines (approximately 0.2 mmol or more) generally cause relaxation of vascular smooth muscles in the presence of various stimulators of contraction (eg, norepinephrine, angiotensin). While relaxation probably results from a reduction of the cytosolic calcium concentration, the extent to which methylxanthines can alter calcium binding and transport, either directly or indirectly, by altering cyclic nucleotide metabolism is unclear.
Thus, adenosine receptor blockade appears to be the predominant mode of action. Methylxanthines act as competitive antagonists at adenosine receptors at concentrations well within the therapeutic range. The effects of exogenous adenosine are frequently opposite to those of the methylxanthines, and the removal of ambient adenosine in some experimental settings (by the addition of adenosine deaminase) can reproduce the actions of the methylxanthines. Plasma concentrations of caffeine that raise blood pressure are within the range for antagonism of adenosine receptors.
Several other caffeine actions that have received relatively little attention to date might prove to be important for certain methylxanthine effects. These include their potentiation of inhibitors of prostaglandin synthesis and the possibility that methylxanthines reduce the uptake and/or metabolism of catecholamines in non-neuronal tissues.
EFFECTS OF CAFFEINE ON THE CENTRAL NERVOUS SYSTEM
In animals, most of the pharmacological effects of adenosine in the brain can be suppressed by relatively low concentrations of circulating caffeine (less than 100 µmol, which is the equivalent of 1-3 cups of coffee). Adenosine decreases the neuronal firing rate and inhibits both synaptic transmission and the release of most neurotransmitters. Caffeine also increases the turnover of many neurotransmitters, including monoamines and acetylcholine.
The A1 and A2a adenosine receptors are the subtypes primarily involved in the caffeine effect, while A2b and A3 receptors play only a minor role. The A1 receptors are linked negatively to adenyl cyclase, while the A2a receptors are linked positively to this enzyme. Adenosine A1 receptors are distributed widely throughout the brain, with high levels in the hippocampus, cerebral and cerebellar cortex, and thalamus. Conversely, A2a receptors are located almost exclusively in the striatum, nucleus accumbens, and olfactory tubercle. In the latter regions, A2a receptors are coexpressed with enkephalin and dopamine D2 receptors in striatal neurons. Direct evidence exists for a central functional interaction between adenosine A2a and dopamine D2 receptors. Indeed, administration of adenosine A2a receptor agonists decreases the affinity of dopamine binding to D2 receptors in striatal membranes.
Interaction between adenosine A2a receptors and dopamine D2 receptors in the striatum might underlie some of the behavioral effects of methylxanthines. By antagonizing the negative modulatory effects of adenosine receptors on dopamine receptors, caffeine leads to inhibition and blockade of adenosine A2 receptors, causing potentiation of dopaminergic neurotransmission. The latter interaction might explain the adenosine receptor antagonists–induced increase in behaviors related to dopamine (eg, caffeine-induced rotational behavior).
CLINICAL TRIALS ON CAFFEINE:
CENTRAL NERVOUS SYSTEM AROUSAL
Quinlan et al from the United Kingdom randomized subjects after
overnight caffeine abstention. In the first study (n=17), the caffeine
level was manipulated by preparing tea and coffee at different strengths
(equivalent of 1-2 cups). Caffeine levels were 37.5 mg and 75 mg in tea
and 75 mg and 150 mg in coffee, and the controls were given water or no
drinks. In the second study (n=15), the caffeine level alone was
manipulated (water or decaffeinated tea plus 0 mg, 25 mg, 50 mg, 100 mg,
and 200 mg of caffeine). Beverage volume and temperature (55 degrees
Celsius) were constant. Systolic blood pressure (SBP), diastolic blood
pressure (DBP), heart rate, skin temperature, skin conductance, and mood
were monitored over 3-hour study sessions.
In study 1, tea and coffee produced mild autonomic stimulation and mood
elevation. Effects were not related to source of caffeine (tea versus
coffee) or caffeine dose, despite a 4-fold variation in the latter.
Increasing beverage strength was associated with greater increases in DBP
and significant arousal. In study 2, caffeinated beverages increased SBP,
DBP, and skin conductance, and lowered heart rate and skin temperature
were noted in those who had water. Significant dose-response relationships
to caffeine were seen only for SBP, heart rate, and skin temperature.
Caffeine had significant effects on arousal but no consistent
dose-response effects. The authors concluded that caffeinated beverages
acutely stimulate the autonomic nervous system and increase alertness. In
addition, caffeine can exert dose-dependent effects on a number of acute
autonomic responses.
Leyner and Horn gave 200 mg caffeine or placebo to young truck drivers
in a double-blind fashion. Caffeine significantly reduced sleep incidents
for the first 30 minutes and reduced subjective sleepiness for an hour.
This caffeine dose (via coffee) effectively reduced early morning driver
sleepiness for about 30 minutes following sleep deprivation and for
approximately 2 hours after sleep restriction.
Ligouri and Grass compared the effects of caffeine on subjective
arousal in introverts and extraverts. Seventeen introverts and 19
extraverts drank coffee that contained caffeine doses of 0 mg/kg, 2 mg/kg,
or 4 mg/kg during morning and evening sessions in a randomized,
double-blind, cross-over design. At 30-minute intervals (for 180 min
postcaffeine dose), participants completed the Profile of Mood States, a
battery of visual analog scales, and the Digit Symbol Substitution Test
(DSST). Caffeine effects on mood and task performance did not
significantly affect extraversion, except for nonsignificant trends for
caffeine to increase happiness and vigor (effect greater in extraverts
than in introverts).
In a study by Herz, the effect of 5 mg/kg of caffeine or placebo on
learning and retrieval sessions was studied, and mood was evaluated by
several self-report measures. Sixteen words were studied during the
learning session, and memory was evaluated by the number of words
correctly recalled at the retrieval session 2 days later. Results revealed
that caffeine reliably increased arousal, but it did not affect any
emotion characteristics related to pleasure. Subjects who received
caffeine at learning and retrieval were in equivalent mood states at both
sessions. Moreover, caffeine did not produce any effects on memory; thus,
neither hypothesis concerning the influence of arousal on memory was
supported by these studies.
A retrospective study examined the benefits of the nonprescription
combination of acetaminophen, aspirin, and caffeine (AAC), eg, Excedrin
Migraine from Bristol-Myers Squibb Company, for the treatment of
menstruation-associated migraine compared with migraine not associated
with menses. Data were derived from 3 double-blind, randomized,
placebo-controlled, single-dose trials enrolling subjects who met the
International Headache Society's diagnostic criteria for migraine with or
without aura. Subjects with incapacitating disability (ie, attacks
requiring bed rest more than 50% of the time) or those who usually
experience vomiting 20% or more of the time were excluded.
Retrospective analysis of the 1220 subjects included in the
efficacy-evaluated data set indicated that 185 women were treated for
menstruation-associated migraine, 781 women were treated for migraine not
associated with menses, and one woman provided no information regarding
menstrual status. At baseline and at 0.5, 1, 2, 3, 4, and 6 hours after
treatment, subjects assessed the intensity of headache pain, functional
disability, nausea, photophobia, and phonophobia. Pain intensity, nausea,
photophobia, and phonophobia were rated on a 4-point scale (ie, 0-3, where
0=none and 3=severe) and functional disability was rated on a 5-point
scale (ie, 0-4, where 0=none and 4=incapacitating).
For both menstruation-associated migraine and migraine not associated
with menses, the proportion of subjects with pain intensity reduced to
mild or none (ie, responders) was significantly greater with AAC than with
placebo at all postdose time points from 0.5-6 hours (P< or =
0.05); treatment effect did not differ significantly between women with
menstruation-associated migraine and women with migraine not associated
with menses at any postdose time point.
Migraine characteristics, such as photophobia, phonophobia, and
functional disability, were significantly improved in AAC-treated subjects
at all time points from 1-6 hours (P< or = 0.01) in both
groups, menstruating women and nonmenstruating women. Significant relief
from nausea was experienced both by women with menstruation-associated
migraine and by women with migraine not associated with menses, but relief
appeared earlier in the nonmenstruating subjects given AAC (2 h postdose,
P< or = 0.01) compared to menstruating subjects (6 h postdose,
P< or = 0.05). Beginning at 3 hours after treatment,
significantly fewer subjects treated with AAC required rescue medication
(P< or = 0.05) for menstruation-associated migraine (AAC 6%,
placebo 15%) and for migraine not associated with menses (AAC 7%, placebo
14%).
The most commonly used rescue medications in both the menstruating and
nonmenstruating groups were nonsteroidal anti-inflammatory drugs,
prescription combination analgesics/narcotics, and prescription migraine
preparations. AAC was well tolerated both in women with
menstruation-associated migraine and in women with migraine not associated
with menses. In general, adverse experiences were similar in both the
groups.
The proportion of subjects who had one or more adverse experiences was
significantly higher among those receiving AAC than among those receiving
placebo (menstruation-associated migraine: AAC 26.4%, placebo 12.6%,
P= 0.025; migraine not associated with menstruation: AAC 18.6%,
placebo 11.4%, P= 0.005). Adverse experiences were similar in
type and severity to those previously associated with a single dose of
acetaminophen, aspirin, or caffeine. Thus, the nonprescription combination
of AAC was shown to be highly effective in treating the pain, disability,
and associated symptoms of both menstruation-associated migraine and
migraine not associated with menses.
The World Health Organization (WHO) and the American Psychiatric
Association (APA) proposed a new set of criteria for dependence. The
diagnosis of dependence requires the fulfillment of 3 (nonspecified) of
the 6 WHO or 7 APA criteria. The 7 criteria of dependence as proposed by
the APA in the Diagnostic and Statistical Manual of Mental
Disorders, 4th edition (DSM-IV), are as follows:
The 6 criteria proposed by the WHO differ only slightly from those of
the APA, with a different sequence, slightly different formulations, and
the combination of criteria 5 and 6. Possible substances of abuse can be
classified according to the number of criteria met and the severity of
symptoms and the frequency of occurrence.
Of 166 caffeine users interviewed, 14% and 3% met the criteria for
moderate and severe caffeine dependence, respectively. Telephone
screenings performed on 99 subjects in the United States found that 16
individuals fulfilled 4 of the 7 criteria cited above and were thus
considered dependent on caffeine. Dependence was not related to daily
caffeine intake, which ranged from 129-2548 mg/day. The median daily
caffeine intake for the caffeine-dependent individuals was 360 mg (40% had
a daily intake of 300 mg or less).
However, despite the absence of current psychiatric disorders at the
time of the study in most of the individuals (14 out of 16), 11 of the 16
persons diagnosed with caffeine dependence had a history of psychiatric
disorders, including substance abuse disorders (10 subjects) and mood
disorders (7 subjects). The prevalence of these disorders was higher in
caffeine-dependent individuals than in the general population (50%). The
tendencies of associations between caffeine, alcohol, and nicotine
consumption, as well as between mood disorders and nicotine dependence,
have been reported previously.
The 4 main factors to consider with regard to the question of
dependence are withdrawal, tolerance, reinforcement, and dependence.
Caffeine withdrawal in animals
Several reports show caffeine withdrawal signs in rats, cats, and
monkeys. These signs include decreases in locomotor activity, operant
behavior, and the reinforcement threshold for electrical brain
stimulation. Other studies show changes in the time spent in various
phases of slow-wave sleep and avoidance of a preferred flavor when the
latter was paired with caffeine abstinence. The severity of caffeine
withdrawal is dose dependent. A decrease in locomotor activity does not
appear when caffeine doses lower than 67 mg/kg/day are substituted for
water. The length of the decrease in locomotor activity also is dependent
on the dose of caffeine and the duration of the treatment before water
substitution. The latency of the onset of caffeine withdrawal effects
occurs within 24 hours and peaks at 24-48 hours. The caffeine
withdrawal–induced behavioral changes last a few days, except for the
sleep-related signs that have been shown to last for as long as 30 days
after the initiation of caffeine withdrawal.
Characterization of withdrawal symptoms in humans
Caffeine withdrawal results in typical symptoms. The most often
reported symptoms are headaches; fatigue; weakness; drowsiness; impaired
concentration; work difficulty; depression; anxiety; irritability;
increased muscle tension; and, occasionally, tremor, nausea, and vomiting.
Withdrawal symptoms generally begin 12-24 hours after sudden cessation of
caffeine consumption and reach a peak after 20-48 hours. In some
individuals, however, these symptoms can appear within only 3-6 hours and
can last for one week.
Withdrawal symptoms do not relate to the quantity of caffeine ingested
daily. For example, Strain et al showed that withdrawal symptoms occur in
individuals consuming 129-2548 mg/day of caffeine. In the last decade, 2
studies suggested that caffeine withdrawal symptoms (but not caffeine
abuse or dependence) should be added to the list of diagnoses recognized
by the American Health System (ie, DSM-IV and International Classification
of Diseases, 10th edition [ICD-10]).
Caffeine consumption, fasting, and headaches before and after surgical
procedures are strongly positively correlated. For every increase in the
usual daily consumption of 100 mg of caffeine (about a cup of coffee), the
risk of headache immediately before and after surgery is increased by 12%
and 16%, respectively, and also correlates with the duration of fasting.
The risk of headaches is reduced in individuals who drink caffeine or
receive caffeine tablets on the day of the surgery. Therefore, permitting
patients who use caffeine and are undergoing minor surgical procedures to
ingest preoperative caffeine may be advisable.
Weber reported that in a similar population, 40-48% of the patients
already suffered regular headaches (at least weekly) at the time of
surgery. Moreover, a relationship exists between caffeine withdrawal,
development of headaches, and changes in cerebral blood flow. Cerebral
blood flow velocities increase during withdrawal headaches, significantly
decrease within 30 minutes of caffeine intake in all subjects, and return
to baseline values after 2 hours. This recent study confirms several
previous studies that suggested that increased blood volume might be
involved in caffeine-withdrawal headaches. Caffeine withdrawal symptoms
were even reported in newborns whose mothers were heavy coffee drinkers
during pregnancy. The infants displayed irritability, increased emotional
activity, and vomiting. Symptoms were present at birth but spontaneously
disappeared after a few days.
Relief of abstinence symptoms by caffeine
Caffeine withdrawal symptoms disappear shortly after ingestion of
caffeine. This effect is linked strongly to the psychological satisfaction
related to the ingestion of caffeine; this is especially true for the
first cup of the day. The potential reversal of caffeine
withdrawal-induced headache and other symptoms by absorption of caffeine
alone has been known for more than 50 years (multiple studies). The
occurrence of headaches following substitution of decaffeinated coffee
predicts subsequent caffeine self-administration. Caffeine content
influences coffee consumption, and the beneficial effects of caffeine
consumption on mood or alertness seem to encourage the consumption of
coffee or caffeine-containing beverages.
Heavy consumers of coffee show a preference for coffee containing
caffeine, while those who typically drink decaffeinated coffee generally
choose either decaffeinated or caffeine-containing coffee. When subjects
are categorized as caffeine choosers and nonchoosers, caffeine choosers
tend to report both positive subjective effects of caffeine (stimulant and
positive effects on mood and vigilance) as well as negative subjective
effects of placebo (headache and fatigue), while caffeine nonchoosers tend
to report negative effects of caffeine (anxiety and dysphoria).
Tolerance to a drug refers to an acquired change in responsiveness
after repeated exposure to the drug. Tolerance can be considered in 2
ways. First, tolerance might indicate that the dose necessary to achieve
the desired euphoric or reinforcing effects increases with time, thus
encouraging increased consumption of the drug. Second, tolerance to the
aversive effects of high doses of the drug may occur, also leading to
increased consumption of the drug over time.
Tolerance to many behavioral effects of caffeine occurs in mice, cats,
and squirrel monkeys treated regularly with methylxanthine. Tolerance to
caffeine-induced locomotor stimulation, cerebral electrical activity,
reinforcement thresholds for electrical brain stimulation,
schedule-controlled response maintained by presentation of food, and
electric shock and thresholds for caffeine- or N-methyl
D-aspartate (NMDA)-induced seizures has been described.
Development of tolerance to caffeine in animals is rapid, usually
insurmountable, and shows cross-tolerance with the other methylxanthines
but not with other psychomotor stimulants such as amphetamines and
methylphenidate. On the first 2 days after caffeine discontinuation,
depression of locomotor activity is noted with a return to baseline values
on the third day (consistent with a withdrawal syndrome). Although the
exact mechanism underlying the development of tolerance to caffeine
remains unclear, tolerance to behavioral effects of caffeine in animals
does not seem to involve adaptive changes in adenosine receptors but may
result from compensatory changes in the dopaminergic system as a result of
chronic adenosine receptor blockade.
In humans, the tolerance to some physiological actions of caffeine can
occur. This is the case for the effect of caffeine on blood pressure,
heart rate, diuresis, plasma adrenaline and noradrenaline levels, and
renin activity. Tolerance usually develops within a few days. Tolerance to
some subjective effects of caffeine, such as tension-anxiety, jitteriness,
nervousness, and the strength of drug effect, has been shown. Conversely,
although tolerance to the enhancement of arithmetic skills by caffeine was
shown recently, evidence of tolerance to caffeine-induced alertness and
wakefulness is limited. These effects are paralleled by the lack of
tolerance of cerebral energy metabolism to caffeine, since acute
administration of 10 mg/kg caffeine induces the same metabolic increase
whether the rats have been exposed to previous daily treatment with
caffeine or saline for 15 days.
Thus, every single exposure to caffeine can produce cerebral stimulant
effects. This is especially true in the areas that control locomotor
activity (eg, caudate nucleus) and structures involved in the sleep-wake
cycle (eg, locus ceruleus, raphe nuclei, reticular formation). In humans,
sleep seems to be the physiological function most sensitive to the effects
of caffeine. Generally, more than 200 mg of caffeine is required to affect
sleep significantly. Caffeine has been shown to prolong sleep latency and
shorten total sleep duration with preservation of the dream phases of
sleep. Whether the difference in the sensitivity to the effects of coffee
on sleep can be attributable to tolerance is not clearly established.
According to some studies, this difference could reflect the individual
sensitivity to caffeine, possibly related to differences in the rate of
caffeine metabolism. Indeed, poor sleepers are reported to metabolize
caffeine at a lower rate. Four of the 10 subjects of the study had
elimination half-lives exceeding 4.8 hours. The variability in response
from one night to the next also should be taken into account.
Nevertheless, some evidence exists of tolerance to caffeine-related sleep
disturbance, since heavy coffee drinkers appear to be less sensitive to
caffeine-induced sleep disturbances than light coffee drinkers. Likewise,
tolerance to sleep latency and quality of caffeine has been shown to
develop over 2 days of testing in one study and over 7 days in another.
However, the tolerance is not complete and the sleep efficiency remains
below 90% of the baseline value after 7 days of caffeine treatment.
Thus, tolerance to some of the effects linked to regular consumption of
coffee seems to occur, especially in animals. In humans, the data are less
conclusive. This may be the result of individual differences in the
susceptibility and tolerance to caffeine-induced effects. Moreover,
mechanisms of tolerance may be overwhelmed by the nonlinear accumulation
of caffeine and its primary metabolites in the human body when caffeine
metabolism is saturated under multiple dosing conditions.
Discrimination of caffeine
Human subjects are able to discriminate caffeine against placebo, both
when dosed in capsules and in coffee. The effects of doses of 300 mg or
higher are detected more easily and primarily are recognized by negative
effects, such as jitteriness, anxiety, or nervousness, whereas lower doses
are detected by their lack of effect or by caffeine withdrawal symptoms.
However, several studies have failed to demonstrate behavioral effects of
caffeine at doses less than 200-300 mg (ie, amounts corresponding to
ingestion of 2-3 cups of coffee). The effects of doses in the range of 100
mg, which closely approaches the caffeine content of a normal serving,
were difficult to detect in one study, and were detected by 30-60% of the
individuals in 2 other studies. However, in most of these studies,
subjects were not withdrawn from their habitual daily intake of caffeine
for a prolonged period of time; thus, tolerance may have played a role.
In fact, doses of caffeine below 100 mg do not induce withdrawal or
negative effects, have rarely been shown to alter self-reports of mood or
performance, and usually are preferred by moderate coffee drinkers. One
study showed discrimination of caffeine at doses as low as 10 mg for one
subject, 18 mg for 3 subjects, and 56 mg for 3 other subjects. This study,
which involved the authors themselves, was replicated with subjects less
informed of the potential effects of the drugs. Data in the same range as
in the previous study were obtained with caffeine discrimination in one
subject at 18 mg of caffeine, in one subject at 32 mg, in 2 subjects at 56
mg, and in 4 subjects at 100 mg caffeine.
The authors suggested that in specific individuals, caffeine could be
considered to affect mood at doses lower than those previously reported.
Indeed, some groups were able to show enhanced auditory vigilance and
reaction time at caffeine doses of 75 mg, 64 mg, or even 32 mg. It seems
that the effects of caffeine are utilized consciously or unconsciously by
various individuals in the management of the mood state relevant to the
context of drink choice. The discrimination of low doses of caffeine is
not related to the taste of caffeine because at the dose of 100 mg,
subjects are not able to reliably differentiate decaffeinated coffee plus
lactose from decaffeinated coffee plus 100 mg of caffeine. Conversely, at
higher doses, caffeine could be detected in coffee because higher
concentrations are related directly to coffee bitterness.
Reinforcing effects of caffeine
Reinforcing efficacy of a drug refers to the relative efficacy in
establishing or maintaining a behavior on which the delivery of the drug
is dependent. In animals, intravenous self-administration of caffeine has
been studied after the implantation of venous catheters that allows
self-administration of the drug by lever pushing and assessment of
behavioral reinforcement. In 4 studies, caffeine was shown to be
self-injected in all animals, while 3 studies showed that only a limited
subset (25-33%) of the animals self-administered caffeine. A sporadic
pattern of caffeine self-administration, characterized by periods with
high rates of self-injection alternating with periods of rather low
intake, was found in nonhuman primates.
Thus, although caffeine seems to be able to act as a reinforcer in some
conditions, a marked difference exists between caffeine and classic drugs
of abuse that maintain self-administration across species and conditions
(eg, amphetamines, cocaine). Recently, caffeine was shown to be able to
reinstate extinguished cocaine-taking behavior in rats. This effect was
more marked when caffeine was given for one day as opposed to 4 days
following the last cocaine self-administration session. Thus, extended
withdrawal increases the priming effects of caffeine. Note, however, that
these animal studies use intravenous self-administration, while human
caffeine consumption is always by oral route, and the former mode of
administration is well known to be by far more addictive than the latter.
For these reasons, caffeine does not appear to be a robust reinforcer in
animals.
In humans, the widely recognized behavioral stimulant and mildly
reinforcing properties of caffeine are probably responsible for the
maintenance of caffeine self-administration, primarily in the form of
caffeinated beverages, such as coffee, tea, and cola. In some studies, the
choice of caffeine has been shown to be controlled more potently by
avoiding withdrawal than by its positive effects, while other data support
the hypothesis that the true performance-enhancing effects of caffeine are
responsible for its self-administration. Most data showed that caffeine
reinforcement occurs in 100% of heavy caffeine consumers (1020-1530 mg/d)
who also have a history of alcohol or drug abuse. For moderate caffeine
users (128-595 mg/d), caffeine reinforcement occurs in 45-100% of
subjects.
Caffeine reinforcement varies with dose. Doses of caffeine in tea and
coffee are high enough to act as reinforcers since these doses can induce
withdrawal symptoms. A dose of 25-50 mg caffeine per cup of coffee acts as
a reinforcer, while increasing doses beyond 50 or 100 mg tends to decrease
the choice of caffeine or the frequency of caffeine self-administration;
high doses of caffeine (400-600 mg in a single dose) are avoided. Caffeine
reinforcement also relates to withdrawal symptoms after the cessation of
coffee. Subjects who consistently suffer from caffeine withdrawal headache
have a 2.6 times higher chance of selecting caffeinated coffee (containing
100 mg caffeine). Caffeine consumption is used to avoid withdrawal more
than it is used for its positive effects.
Bickel reviewed 16 studies dealing with the behavioral economics
paradigm for the study of drug abuse. Increasing consumption of a
fixed-price item when a similar item becomes more expensive indicates a
substitutive function and is seen clearly with opiates, cocaine, and
phencyclidine but not with caffeine. These data confirm that caffeine is
less reinforcing than amphetamine and related psychomotor stimulants.
Reinforcing effects of caffeine-containing drinks unrelated to
caffeine
The conditions under which caffeine functions as a reinforcer are still
not clearly understood. However, the possible reinforcing effects of
coffee unrelated to caffeine include its aroma, taste, and social
environment in which it is consumed. Subjects with a habitual coffee
consumption of 4-10 cups per day (mean intake 6 cups per day) were
switched, without a withdrawal period, to the consumption of 600 mg of
caffeine, either in tablets containing 50 mg of caffeine each or
decaffeinated instant coffee for 3 days. The desire for coffee in the next
3 days largely increased in the group given caffeine tablets but remained
unchanged in the group given decaffeinated instant coffee, although the
latter group experienced marked caffeine withdrawal symptoms.
The question of whether the taste of coffee and caffeine may influence
its intake is still a matter of debate. If water-containing caffeine is
given regularly to rats between 29 and 40 days of postnatal life, these
rats, as adults, will drink more caffeinated water than tap water.
Likewise, the previous administration of an adenosine agonist increases
caffeine intake.
Thus, caffeine intake could, at least partly, be related to its
pharmacological properties, though the influence of taste cannot be
eliminated. In fact, coffee and caffeine have 2 components, appetitive and
aversive. The absorption of low quantities of caffeine could favor the
appetitive effect of caffeine, whereas higher quantities could exacerbate
its aversive effects. In humans, the gustatory response to caffeine is not
influenced by previous exposure to a series of methylxanthines, adenosine,
or caffeine deprivation. However, the taste of coffee is an important
aspect of caffeine consumption; subjects prefer caffeine in coffee to
caffeine in capsules.
Also, another possibility is that caffeine is a constituent of coffee
and tea, which are liked by users for reasons independent of their
caffeine content. Thirst may be one factor but is probably not a major
factor in the consumption of tea or coffee (though it could contribute to
the consumption of soft drinks). An affinity for sensory properties of tea
and coffee also can be related to the nutritional benefit derived from the
milk, cream, and/or sugar added to the beverage.
The last possibility is the influence of situational conditions on mood
that can play an important role in reinforcing preferences for specific
foods and beverages. Indeed, coffee and tea often are consumed in social
contexts and during breaks from work. Therefore, the influence of caffeine
on the consumption of tea, coffee, or soft drinks may be relatively subtle
and depends both on the cumulated dose over the day and the mood state in
which it is consumed. For example, if an individual is already quite
stimulated, ingestion of a caffeine-containing beverage may lead to
unpleasant effects. Recent findings showed that, in some individuals, the
choice to drink coffee is influenced by the interaction between the mood
state before drinking coffee and the anticipated effects based on the
content of caffeine in the drink.
Clearly, further studies are required to better define both the short-
and long-term roles of caffeine in the neurological and cardiovascular
systems. The combined results of these future studies will be of keen
interest to all those who enjoy that warm cup (or multiple cups) of coffee
to start the morning.
REFERENCES
MEDCEU
Continuing Education Courses CEU for Nurses and Healthcare Professional
In
a Dutch study, event-related potentials were recorded from 11 subjects
after administering caffeine (250 mg) or placebo. Subjects were instructed
to attend selectively to stimuli with a specified color (red or blue) in
order to react to the occurrence of a target within the attended category.
Reaction times revealed faster responses in subjects who had been
administered caffeine, whereas no differences in strategy were observed
between the 2 groups. This study suggested that caffeine results in a
higher overall arousal level, more profound processing of both attended
and unattended information, and acceleration of motor
processes.
In a study conducted by Bertini et al, preterm
infants with a gestational age of less than 32 weeks and birth weight of
less than 1500 g were randomized to receive either caffeine or
aminophylline treatment for apnea of prematurity. This study concluded
that caffeine does not significantly affect brain hemodynamics, while
aminophylline induces a significant transient increase in oxygenated
hemoglobin (HbO2) and cerebral blood volume (CBV).
Migraine
headaches
Drug dependence
is defined as a pattern of behavior focused on the repetitive and
compulsive seeking and taking of a psychoactive drug.
Potential model of drug of abuse
Withdrawal
Tolerance
Discrimination and reinforcement
Caffeine is contained in some of the
most widely consumed foods and beverages, both in the United States and
internationally. For this reason, it has been extensively investigated in
both animal models and human studies. Although caffeine shares some
characteristics with other chemicals of abuse with regard to both
psychological and physiological dependence, important differences exist,
especially pertaining to the action of caffeine in CNS neurotransmitter
systems.