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Biology 202, Spring 2005 Second Web Papers On Serendip

More Than a Cup of Joe: Clinical Implications for the Neurobiology of Caffeine

Joanna Scott

Caffeine is perhaps best associated with its 'energy-boosting' powers—its effects on alertness and memory. Many avid coffee drinkers swear they cannot function properly without it. Indeed, its benefits have been touted for years and new studies are further expanding the list of its useful properties. Understanding caffeine's mechanism of action in the brain is a helpful start in determining its relationship to different aspects of health and overall functioning. When the majority of coffee drinkers go to the office coffee pot or to line up at Starbucks, however, chances are their motivation is not to reduce their risk of Parkinson's disease. Therefore, understanding the neurobiology behind caffeine and its benefits or risks is only the first step. We must next consider how to use this information in a clinical setting.

Caffeine is a widely used central nervous stimulant found most commonly in coffee, tea, soda, and chocolate, but also in such over-the-counter medications as pain relievers and cold medicines. Current consumption levels average 200 mg/daily for adults (2). Caffeine belongs to the pharmacological class of compounds called methylxanthines. Its primary mechanism is as an adenosine receptor antagonist. Adenosine is involved in important biochemical processes such as energy transfer and signal transduction (12). The inhibitive effects of caffeine on adenosine are fairly specific, occurring mainly in the A2A receptor subtype in dopamine-rich areas of the brain (1). Activation of adenosine receptors, such as A2A, inhibits the neurotransmitter dopamine. Dopamine is involved in carrying out motor movements, and has also been implicated in (4) Caffeine indirectly increases levels of dopamine in such areas as the meso-limbic and nigra-strital pathways through its suppression of adenosine (8). Observational studies have found that caffeine may have a neuroprotective effect against Parkinson's disease (PD). Depleted levels of dopamine in such areas a(10). Ross et. al (2000) noted that nondrinkers of coffee had a risk for developing PD 2-3 times higher than that of coffee-drinkers. Similarly, Gale and Martyn (2003) reported a 30% risk reduction for PD in coffee drinkers compared to non-drinkers. Whether or not increases in dopamine related to caffeine intake will help clinicians to treat Parkinsonian symptoms has yet to be determined; for now, the data is restricted to the observational and correlative.

Regular coffee drinkers have also shown a decreased risk for diabetes, gallstones, and colon cancer, along with improvements in cognitive functioning (6). While the wide held belief that drinking coffee will help treat a hangover appears unfounded, caffeine's effects on general arousal and on more specific perceptual, attentional, and motor processes are not just a myth. This is the 'upper' the general public associates with caffeine and these benefits have been supported by previous research (11). Most of these effects are transient, however, usually lasting only a few hours. Both a stimulant and diuretic, caffeine has a half-life of several hours. That is, half of the amount consumed is leaves the bloodstream in 3-4 hours. Caffeine may have other uses beyond the effects of mere consumption. Sheppard, Grace, Cole, & Klein (2005) gave a group of students a decaffeinated beverage, but told them the study was examining the effects of caffeine on academic performance. In one condition, the students were told, prior to receiving feedback on performance, that the coffee they drank was highly caffeinated and that they may experience some trembling, increased perspiration, and feelings of anxiety. This was part of a misattribution paradigm in which the students were led to attribute any anxiety they felt to the coffee. The researchers found the misattribution paradigm successfully boosted students' optimism and helped them cope with their apprehension (p. 273). When given an external 'cause' for their anxious feelings, participants attributed their sensations to that 'cause'—the caffeine—and not to the anticipation of negative feedback.

The misattribution paradigm might be a useful tack for clinicians to try when working with ruminators or prior to giving patients results of medical exams. The very experience of anxious symptoms can trigger further anxiety about those symptoms (positive feedback loop). For example, patients might feel their heart race or shortness of breath and then worry they are going to die or have a panic attack, and that increases the heart rate and so forth. Perhaps the coffee can be used to interrupt such a cycle; patients can reassure themselves that their feelings have a tangible cause and will pass soon. If a patient is worried about test results, such a paradigm could allow them to attribute their anxiety to the caffeine and feel more optimistic about their tests. One important caveat: caffeine is associated with increases in agitation and anxiety. While this makes it a believable cause for anxious feelings, it might exacerbate some patients' conditions and so clinicians should encourage anxiety sufferers to limit their caffeine intake. Another consideration is that of interactions between caffeine and medications such as SSRIS and MAOIs (antidepressants). As mentioned above, caffeine is linked to increases in dopamine. Monoamine oxidase inhibitors (MAOIs) also increase dopamine levels, by interfering with the enzyme (MAO) which breaks down dopamine at the synapse. Abnormalities in neurotransmitter functioning are believed to be at the root of many mental disorders; long-term use of caffeine may further disrupt this functioning and complicate pharmacological treatments. In summary, the misattribution paradigm may be useful, but better suited to another external cue than caffeine or for patients without chronic anxiety concerns.

Caffeine intake will soon be relevant to clinicians for another reason: addictive potential. There are plans to include caffeine withdrawal in the upcoming DSM-V, expected to be released in 2011 (5). A study by Johns Hopkins University concluded that caffeine withdrawal is "a veritable syndrome"; as many as half of regular consumers of caffeine will experience withdrawal in the absence of their usual dose (6). Headache, fatigue, nausea, irritability, and difficulty concentrating are the common symptoms associated with caffeine withdrawal. These symptoms are the result of adenosine. If we think of the effects of caffeine as the opposite of adenosine, withdrawal can be viewed as the "reversal of those effects with a vengeance" (6). While adenosine dilates the blood vessels, caffeine restricts them. When the caffeine leaves the bloodstream, the blood flow increases again, causing the unpleasant feelings of a headache. In regular consumers, the desire for caffeine may be more of an attempt to reduce the unpleasant side effects of withdrawal than to experience its benefits. Physiological dependence has two components: withdrawal and tolerance. Regular caffeine users do exhibit tolerance. Compared to infrequent users, who get a 'buzz' from one cup of coffee, regular coffee- drinkers will often need two or three cups to produce the same response (2). This is the very definition of tolerance—requiring more of the substance over time to produce the same effect. People show varying levels of sensitivity to caffeine. Interestingly, dependency is not correlated with amounts of caffeine consumed in either adults or adolescents. Some adults showing tolerance and withdrawal actually drink less than the national average (1). Despite these 'addictive' properties, caffeine consumption is socially accepted and, at times, even encouraged. Visiting Starbucks is trendy, and the notion of 'coffee hour' or 'coffee talk' has established a firm relationship between caffeine consumption and social interaction. Potentially reinforcing properties of caffeine include such social interaction, as well as the increases in dopamine, the energy boost (or 'buzz'), and even the pleasant aroma.

At first glance, caffeine withdrawal does not seem overly alarming, just mildly unpleasant. The real concern arises from the studies suggesting that caffeine could be a gateway drug. Animal studies support that caffeine facilitates the effect of self- administration of other drugs, such as nicotine and cocaine (1). There is a potential confound here, however, as nicotine increases the metabolism of caffeine (7). Smokers may therefore have more tolerance to caffeine. The theory of an 'addictive personality' is not a new one. Different addictions do overlap, or co-occur in predictable ways. For example, Christo, et al. (2003) noted that college students' use of alcohol, nicotine, caffeine, chocolate, exercise, and gambling were highly correlated. Individuals showing addiction to one substance or activity seem to have an increased risk for developing further addictive behaviors. A common, underlying pathway—such as dopamine-- might be involved in all such behaviors. Psychoactive substances and behaviors that increase physiological arousal (gambling or exercise) may be linked to increased sensation-seeking or impulsivity in general. Christo, et al. (2003) found that one-third of bulimics indicated "problematic use of caffeine". The same was true for 36.8% of alcohol and drug users (p. 236).

Whether or not caffeine constitutes a gateway drug is still highly debatable. Caffeine is currently the most commonly ingested psychoactive substance (1). This means that by sheer numbers alone, regular caffeine users are well represented in most populations. The actual percentage of such consumers that go on to develop more serious addictions, to the point of hurting loved ones and neglecting their responsibilities, is presumably low. Coffee drinking is not usually associated with guarding of the supply, or stealing in order to attain coffee, and so forth. Problematic psychological caffeine addiction may be qualitatively different from physiological dependence on caffeine and represent a population at risk for other addictive behaviors. Clinicians should be aware of the correlation, and assess their clients' intake of various substances, as well as their motivation for such use. On the positive, the social aspects of caffeine could be used constructively in some clients who would benefit from the basic human interactions that occur in such places as the coffee shop. And if there are concerns about anxiety and insomnia, they can even make it a decaf!


1)Bernstein, G. A., Carroll, M. E., Thuras, P. D., Cosgrove, K. P., & Roth, M. E. (2002). Caffeine dependence in teenagers. Drug and Alcohol Dependence, 66, pp. 1-6. Article Online

2)Caffeine and Health: Clarifying the Controversies. 1993.International Food Information Council.

3)Christo, G., Jones, S. L., Haylett, S., Stephenson, G. M., Lefever, R. M. H., & Lefever, R. (2003). The shorter PROMIS Questionnaire: Further validation of a tool for simultaneous assessment of multiple addictive behaviors. Addictive Behaviors, 28, pp. 225-248. Article Online.

4) Dopamine - A Sample Neurotransmitter. , University of Texas at Austin's Review of DA

5)The DSM-V Prelude Project. , The APA's Updates on the DSM-V

6) Crazy for Coffee. , Psychology Today's Overview of Coffee

7)Gale, C. and Martyn, C. (2003). Tobacco, caffeine, and Parkinson's disease. British Medical Journal, 326, 561-562. Article Online.

8)Ross, G. W., Abbott, R. D., Petrovich, H., Morens, D. M., Grandinetti, A., Tung, K., Tanner, C. M., Kamal, H. M., Blanchette, P. L., Curb, J. D., Popper, J. S., & White, L. R. (2000). Association of coffee and caffeine intake with the risk of Parkinson Disease. Journal of the American Medical Association, 283 (20), pp. 2674-2679.

9)Sheppard, J. A., Grace, J., Cole, L. J., & Klein, C. (2005). Anxiety and outcome predictions. Personality and Social Psychology Bulletin, 31(2), pp. 267-274.

10)The Substantia Nigra in PD., from WEMOVE--Worldwide Education and Awareness for Movement Disorders

11)Tieges, Z., Ridderinkhof, K. R., Snel, J., & Kok, A. (2004). Caffeine strengthens action monitoring: Evidence from the error-related negativity. Cognitive Brain Research, 21, pp. 87-93. Article Online

12) Image of the Molecule Adenosine, from Wikipedia Online

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