In western societies caffeine is the elixir of mind which grants vigilance to those who consume it. It has become a commonplace item, consumed each morning and afternoon to reduce those feelings of fatigue from heavy work or lack of sleep. How does it work however? What are its benefits other than the immediate?
Mechanism of Action
Schematic illustration of the effect of caffeine on striatopallidal and striatonigral neurons.
A, potential interactions between A2A and D2 receptors in the GABAergic neurons that comprise the so-called indirect pathway and project to the ventral pallidum.
B, a simplified wiring diagram of the nucleus accumbens and some of its input and output structures. Synapses are shown as stimulatory (●) or inhibitory (○). In this part of the figure are also indicated areas where adenosine and dopamine receptor subtypes are enriched.
C, the interactions between A1, D1, and glutamate receptors in neurons that comprise the so-called direct pathway. In particular, it should be noted that activation of dopamine D1 receptors can enhance the actions mediated via NMDA receptors. This causes release of adenosine, which activates A1 receptors located on the terminals of the excitatory input. Hereby the release of glutamate is reduced.[6]
Of the known biochemical actions of caffeine, only inhibition of adenosine receptors occurs at concentrations achieved during normal human consumption of the drug. Under normal physiological conditions, adenosine is present in sufficient concentrations to activate A1 and A2a receptors. Via actions on A, receptors, adenosine decreases neuronal firing and the release of neurotransmitters. The exact mechanisms are not known, but several possibilities are discussed. Via actions on A2a receptors, adenosine - and hence caffeine - can influence dopaminergic neurotransmission. Caffeine can induce rapid changes in gene expression and, somewhat later, marked adaptive changes. These include antiepileptic and neuroprotective changes. Thus, caffeine has a number of central effects directly or indirectly related to adenosine receptors. Some of these are potentially useful, and drug development based on the actions of caffeine should be interesting.[2]
Caffeine, in substantive amounts, is frequently taken by the clinical or hospitalized patient. Caffeine content of coffees, teas, cola drinks, cocoa, and drugs is summarized. Systems and organs affected by caffeine include the central nervous system, the cardiac muscle, the kidney, the gastric mucosa, and smooth muscle. Psychotropic and sleep response varies with age and degree of habituation. Symptoms of caffeinism, caffeine withdrawal, and caffeine-drug interactions are described.[5]
In fact, the only known mechanism that is significantly affected by the relevant doses of caffeine is binding to adenosine receptors and antagonism of the actions of agonists at these receptors (see Fredholm, 1980, 1995). Thus, in the remainder of this section, adenosine receptor antagonism is taken to be themechanism of action of caffeine even though there are data, especially from behavioral experiments, that could be interpreted as evidence for some other, as yet unidentified mechanism of action (see, e.g., Garrett and Holtzman, 1995).[6]
It is also known that caffeine increases the turnover of several monoamine neurotransmitters, including 5hydroxytryptamine (5-HT) dopamine, and noradrenaline (Fernström and Fernström, 1984;Bickford et al., 1985; Fredholm and Jonzon, 1988; Hadfield and Milio, 1989). There is evidence that methylxanthines increase the rate of firing of noradrenergic neurons in the locus ceruleus (Grant and Redmond, 1982). The increase in noradrenaline turnover is probably the explanation for the fact that methylxanthines also reduce the number of β-adrenoceptors in rat brain (Fredholm et al., 1984; Shi et al., 1993a). It has also been shown that the mesocortical cholinergic neurons are tonically inhibited by adenosine and that caffeine consequently increases their firing rate (Rainnie et al., 1994). It was postulated that this effect is of importance in the electroencephalogram (EEG) arousal following caffeine ingestion. Because dopamine and noradrenaline neurons also are involved in arousal, there is ample neuropharmacological basis for assuming that central stimulatory effect of caffeine could be related to inhibition of adenosine A1 receptors. Also there are increases in 5-hydroxytryptamine receptors, muscarinic receptors, and δ-opioid receptors following higher doses of caffeine (Shi et al., 1993a, 1994). The functional relevance, if any, of these changes remains to be elucidated.[6]
Benefits
Parkinson's Disease
Results of case-control studies and of a prospective investigation in men suggest that consumption of coffee could protect against the risk of Parkinson's disease, but the active constituent is not clear. To address the hypothesis that caffeine is protective against Parkinson's disease, we examined the relationship of coffee and caffeine consumption to the risk of this disease among participants in 2 ongoing cohorts, the Health Professionals' Follow-Up Study (HPFS) and the Nurses' Health Study (NHS). The study population comprised 47,351 men and 88,565 women who were free of Parkinson's disease, stroke, or cancer at baseline. A comprehensive life style and dietary questionnaire was completed by the participants at baseline and updated every 2-4 years. During the follow-up (10 years in men, 16 years in women), we documented a total of 288 incident cases of Parkinson's disease. Among men, after adjustment for age and smoking, the relative risk of Parkinson's disease was 0.42 (95% CI: 0.23-0.78; p for trend < 0.001) for men in the top one-fifth of caffeine intake compared to those in the bottom one-fifth. An inverse association was also observed with consumption of coffee (p for trend = 0.004), caffeine from noncoffee sources (p for trend < 0.001), and tea (p for trend = 0.02) but not decaffeinated coffee. Among women, the relationship between caffeine or coffee intake and risk of Parkinson's disease was U-shaped, with the lowest risk observed at moderate intakes (1-3 cups of coffee/day, or the third quintile of caffeine consumption). These results support a possible protective effect of moderate doses of caffeine on risk of Parkinson's disease.[3]
Endurance
The effect of different dosages of caffeine (0 - 5 - 9 - 13 mg · kg body weight-1) on endurance performance was examined. Nine well-trained cyclists participated in this study (VO2max 65.1 + 2.6 ml · kg-1 · min-1). Caffeine capsules were administered in random order and double-blind. One hour after capsule ingestion, subjects cycled until exhaustion at 80 % Wmax on an electromagnetically braked cycle ergometer. Blood samples were taken before, during and after the exercise test. Before and after the test a urine sample was obtained. A significant increase in endurance performance was found for all caffeine tests compared to placebo (endurance time 47 + 13, 58 ± 11, 59 ± 12 and 58 ± 12 min for 0, 5, 9 and 13 mg kg-1 body weight, respectively). No differences were found in endurance performance between the three caffeine dosages which indicates that no dose-response relation of caffeine and endurance performance was found. An increased free fatty acid and glycerol concentration was found after caffeine consumption compared with placebo. The mean urinary caffeine concentrations after exercise were 4.8 + 1.8, 8.9 ± 5.2 and 14.9 ± 6.9 μg ml-1 urine for 5, 9 and 13 mg of caffeine kg-1 body weight. Only the lowest dose of caffeine resulted in urine caffeine concentrations below the doping limit of the International Olympic Committee of 12 μg ml-1 urine in all individuals. It is concluded that caffeine is an ergogenic aid that stimulates endurance performance. A dose-response relation between caffeine and endurance time was not found for the dose-range investigated. The stimulating effect of caffeine was already apparent at the lowest dose of caffeine given (5 mg kg-1). At this dose urinary caffeine concentration remained below the doping limit in all subjects.[4]
Uncertainties
On learning
An array of studies found that caffeine could have nootropic effects, inducing certain changes in memory and learning.
Researchers have found that long-term consumption of low dose caffeine slowed hippocampus-dependent learning and impaired long-term memory in mice. Caffeine consumption for 4 weeks also significantly reduced hippocampal neurogenesis compared to controls during the experiment. The conclusion was that long-term consumption of caffeine could inhibit hippocampus-dependent learning and memory partially through inhibition of hippocampal neurogenesis.[102].
In another study, caffeine was added to rat neurons in vitro. The dendritic spines (a part of the brain cell used in forming connections between neurons) taken from the hippocampus (a part of the brain associated with memory) grew by 33% and new spines formed. After an hour or two, however, these cells returned to their original shape.[103]
Another study showed that human subjects — after receiving 100 milligrams of caffeine — had increased activity in brain regions located in the frontal lobe, where a part of the working memory network is located, and the anterior cingulate cortex, a part of the brain that controls attention. The caffeinated subjects also performed better on the memory tasks.[104]
However, a different study showed that caffeine could impair short-term memory and increase the likelihood of the tip of the tongue phenomenon. The study allowed the researchers to suggest that caffeine could aid short-term memory when the information to be recalled is related to the current train of thought, but also to hypothesize that caffeine hinders short-term memory when the train of thought is unrelated.[105] In essence, caffeine consumption increases mental performance related to focused thought while it may decrease broad-range thinking abilities.[1]
Risks
Anxiety and sleep disorders
Two infrequently diagnosed caffeine-induced disorders that are recognized by the American Psychological Association (APA) are caffeine-induced sleep disorder and caffeine-induced anxiety disorder, which can result from long-term excessive caffeine intake.
In the case of caffeine-induced sleep disorder, an individual regularly ingests high doses of caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention.[92]
In some individuals, the large amounts of caffeine can induce anxiety severe enough to necessitate clinical attention. This caffeine-induced anxiety disorder can take many forms, from generalized anxiety to panic attacks, obsessive-compulsive symptoms, or even phobic symptoms.[92] Because this condition can mimic organic mental disorders, such as panic disorder, generalized anxiety disorder, bipolar disorder, or even schizophrenia, a number of medical professionals believe caffeine-intoxicated people are routinely misdiagnosed and unnecessarily medicated when the treatment for caffeine-induced psychosis would simply be to stop further caffeine intake.[100] A study in the British Journal of Addiction concluded that caffeinism, although infrequently diagnosed, may afflict as many as one person in ten of the population.[88] Co administration of theanine was shown to greatly reduce this caffeine-induced anxiety.[101][1]
Possible Harmful Effects of Caffeine at the Individual or Social Level—Abuse or Misuse
Negative social consequences of coffee drinking are not claimed, but DSM-IV (1994) lists caffeine intoxication, caffeine-induced anxiety, and sleep disorders as caffeine-induced disorders.References
Despite its wide availability, caffeine intoxication occurs rarely. The lethal dose has been estimated to be in the range of 10 g (Ritchie, 1975), which would correspond to about 100 strong coffees. Provided adequate emergency measures are taken, patients appear to survive levels up to 1 mM or even slightly above, but still higher levels are fatal (Rivenes et al., 1997). Among the 3749 cases of “caffeine exposure”, registered during 1 year by the American Association of Poison Control Centers, there were only three fatalities (Litovitz et al., 1987).
Although caffeine overdoses can induce anxiety, there is little and in part controversial evidence as to whether coffee might play a significant role in this disorder (see above Section IVB). No significant association between anxiety and coffee or tea consumption was seen in a US nationwide sample of 3854 subjects (Eaton and McLeod, 1984) or in an English sample of 9003 individuals (Warburton and Thompson, 1994). The same negative result holds also for depression (Warburton and Thompson, 1994), confirming the results of an earlier larger study (Jacobsen and Hansen, 1988). One possible explanation for this failure to find relationships between coffee drinking and anxiety may be that anxious subjects avoid coffee. In fact, avoidance of coffee by anxious subjects has been reported repeatedly over the last decades (Boulenger et al., 1984; Uhde et al., 1984; Lee et al., 1985). A review on putative correlations between sleep disorders or insomnia and caffeine consumption would yield a similarly controversial picture, as discussed above in the chapter on tolerance for the sleep-disturbing effects of caffeine. As in the case of anxiety, it appears that by far the most consumers of coffee adapt their intake both with respect to time of day and dosage so as to avoid acute sleep disturbance or chronic insomnia.
When people are interviewed about psychoactive substance use disorders, seven criteria are used: 1) tolerance; 2) withdrawal; 3) substance often taken in larger amounts or over a longer period than intended; 4) persistent desire or unsuccessful efforts to cut down or control use; 5) a great deal of time spent in activities necessary to obtain, use, or recover from the effects of the substance; 6) important social, occupational, or recreational activities given up or reduced because of substance use; 7) use continued despite knowledge of a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by substance use. Because coffee or caffeine-containing nutrients or drinks are widely available and culturally accepted, their consumption does not usually have negative social consequences. Indeed, in the studies on caffeine dependence, criteria 3, 5, and 6 are usually excluded. Especially in the US there is no doubt that many individuals reduce or try to reduce their caffeine intake due to perceived health problems (see Hughes and Oliveto, 1997). Indeed, not less than 14% of all erstwhile consumers in Vermont had stopped the intake of all caffeine-containing beverages largely for this reason (Hughes and Oliveto, 1997). This relates to criterion 7 if these individuals have difficulties in reducing intake. One interesting question is therefore if caffeine poses a real health hazard or if the negative association between health and caffeine is a perceived one.
Considering the individual consequences, caffeine-induced dysphoria and nervousness could negatively influence the relationship of some individuals in the society. However, this aspect of caffeine consumption does not seem very pertinent.
The possibility that caffeine consumption may pose major health risks has been widely discussed (see James, 1991). Caffeine does raise mean arterial blood pressure by a few millimeters of mercury; this has been suggested to pose a health risk by some (James, 1991), but not by others (Tuomilehto and Pietinen, 1991). More recently, greater concern has been voiced about the ability of caffeine to raise plasma cholesterol (Thelle et al., 1983, 1987). It is now known that the increase in plasma cholesterol is due to two diterpenes: cafestol and kahweol (see Urgert and Katan, 1997). These compounds are largely eliminated when coffee is prepared by filtration or percolation or from instant coffee. By contrast, boiled coffee and Turkish coffee, and to a lesser extent espresso and mocha coffee, do contain these diterpenes and have been shown to raise cholesterol levels by some 0.1 to 0.5 mM during prolonged use (see Urgert and Katan, 1997). The rather low intake of these brews suggest that coffee contribution to overall cardiovascular risk is small (Myers and Basinski, 1992; Greenland, 1993; Kawachi et al., 1994; Willett et al., 1996), even though it has been calculated that the large-scale switch from boiled to filtered coffee might have contributed to a third to half of the 10% reduction in serum cholesterol noted in Scandinavia since 1970 (Johansson et al., 1996b; Pietinen et al., 1996).
Another potential factor in predicting cardiovascular risk is plasma homocysteine. It was recently shown that, although coffee drinking per se has a limited effect on this variable, combined smoking and high coffee drinking was associated with an increased number of subjects with very high plasma homocysteine levels (Nygård et al., 1998). It is, however, too early to decide on the importance of these findings, particularly because the relevant intervention studies have not been performed.
There are several reports showing that very high doses of caffeine can have mutagenic or carcinogenic effects (see Mohr et al., 1993). This has raised concerns about cancer risks following normal caffeine consumption, but a careful consideration of the evidence “provides further reassuring information on the absence of any meaningful association of coffee with most common cancers” (La Vecchia, 1993).
Although there is a public perception (especially in the US) that caffeine is detrimental to one’s health, this has a surprisingly weak basis in reality. On the other hand, health problems from other causes might provide an incentive to cease caffeine consumption, especially in the form of coffee. If this is true, then ex-caffeine consumers may constitute a subgroup with more health problems than the average population. This could be a concern in the interpretation of some epidemiological studies.[6]
[1] Wikipedia: Caffeine
[2] Adenosine, Adenosine Receptors and the Actions of Caffeine
[3] Prospective study of caffeine consumption and risk of Parkinson's disease in men and women
[4]The Effect of Different Dosages of Caffeine on Endurance Performance Time
[5]Physiologic and psychotropic effects of caffeine on man. A review.
[6]Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use
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