In response to a couple of questions about the implications of long-term caffeine intake, I’d thought I’d throw out a couple of findings.
I recently wrote about a study that localized the receptors underlying the arousing effects of caffeine. (A2a receptors, in cells located in the shell of the nucleus accumbens). It’s only natural then to wonder what effect chronic caffeine intake might have on these receptors (and elsehwere in the brain).
That study didn’t look at chronic effects. But back in 1996, Glass et al. found that chronic caffeine consumption increased the global expression of adenosine receptors in the brain , suggesting that this increase was to compensate for caffeine’s antagonistic effects. Withdrawal from caffeine is, at least in part, likley related to a hypersensitivity to adenosine due to this increased number of adenosine receptors. The headaches that accompany caffeine withdrawal are thought to be related to the fact that adenosine is a known vasodilator and the increased receptor density + withdrawal of caffeine from the system leads to a significant drop in blood pressure.
A couple other interesting notes in regards to long-term effects of caffeine:
The Good News
Some case control studies have shown lower incidents of Parkinson’s disease in coffee drinkers vs. non-coffee drinkers, although this finding has not always been replicated. The correlation, when it has been found, was strongest in heavy consumers. (This is certainly a finding I would love to be true!) More evidence in support of these findings come from mouse studies showing that physiological doses of caffeine were able to reduce one of the major toxic factors associated with Parkinsons (MPTP-induced dopaminergic toxicity). It’s been suggested that caffeine may offer neuroprotective effects in the brain via action occurring at A2a receptors, which are the same receptors responsible for the arousing effect of caffeine (and which are also co-localized with dopamine D2 receptors). Additional support for this idea comes from studies in which mice who had their A2a receptors knocked out showed reduced MPTP-induced injury compared to wild types. How this all might be happening on a mechanistic level, however, is not well known.
The less good (but not totally bad) news:
Unfortunately, it seems that acute doses of caffeine often cause a rise in systolic and diastolic blood pressure, increase in catecholamine release and vasodilation (wideneing of blood vessels). However, some studies have shown this effect occurs primarily in non-regular consumers of caffeine. Many studies have shown either slight increases or no difference in blood pressure for regular users of caffeine. In fact, several large scale studies have found that heavy, regular use is protective against heart disease. (yes!) The findings are quite contradictory.
So what to make of all this? Is heavy coffee drinking bad or good for you?
There’s no simple answer to that question. But the paradoxical findings suggest that different individuals have varying levels of risk. And it’s likely that genetics play a significant role.
If one thinks of coffee as a drug, then the notion that the benefits of heavy coffee consumption might outweigh the risks seems very counterintuitive. That is, due to the brain’s propensity to maintain homeostasis, drug taking, either legal or illegal, usually involves some significant cost/benefit analysis, a trade off between the good (the high, buzz, relief from psychic or physical pain) and the bad (side effects, withdrawal, expense, long-term effects on health). Yet, the evidence on long-term caffeine intake seems to put it in a distinctive class of its own.
I once chatted with an extremely energetic and sprightly 93-year old Italian man from the old country, curious to know the the secret to his longevity and good health. “Five espressos a day,” he said. Anecdotes aren’t very informative in an empirical sense, of course, but, nonetheless, the old codger may have been on to something.*
* In addition to the espressos, he’d also claimed that he smoked a pack a day of American Winstons and was convinced that brand loyalty was one of the other secrets to his good health.
Have you ever wondered why, and exactly where in the brain, coffee (or any caffeinated product, for that matter) is able to exert its arousing effects? Well, wonder no longer, because an international team of researchers from Japan, China and the US, have located the primary neurons upon which caffeine works its magic (Lazarus 2011).
It was previously known that caffeine wakes you up through inhibiting activity at adenosine A2a receptors (adenosine is an inhibitory neuromodulator involved in regulating the sleep-wake cycle). However, it was not known exactly where in the brain the receptors that exerted this effect are located.
How did they do it?
The researchers utilized a method whereby the gene that codes for A2a receptors (A2aRs) is marked such that they can be deleted, but only in a specific regions of the brain. Using a rat model, the team utilized these gene deletion strategies and found that when they knocked out A2aRs in the shell of the nucleus accumbens, rats no longer experienced the arousing effects of caffeine.
How does this work?
Adenosine activates A2a receptors in the nucleus accumbens shell, activation of which receptors inhibit the arousal system. That is, the more adenosine activation there is, the sleepier an organism becomes. Caffeine, which binds to these same receptors and blocks adenosine from exerting its activity there, essentially disinhibits the arousal system, promoting wakefulness. (Amazingly, based on similarities between the brains of mice and men, the area of the human brain in which caffeine acts to counteract fatigue is approximately the size of a pea.)
What does this mean in practical terms? (or, in other words, why should we find this so cool?)
Well, for one, it gives us a more specific mechanistic explanation for the arousing effects of caffeine. It says that in order for caffeine to work, it not only has to be effective as an A2aR antagonist, but that excitatory A2aRs on nucleus accumbens shell neurons must be tonically activated by endogenous adenosine. This is especially important in consideration of individual differences in the subjective effects of caffeine.
What if A2aRs are more densely packed in the shell of your nucleus accumbens than in mine? Might you be more sensitive to the effects of caffeine than me? That certainly seems likely. And the reason that one person might over or underexpress these receptors vs. another seems to be related to variation in the gene that produces those receptors (the gene knocked out in the rat study described above). In fact, we’ve already have evidence that this is the case. Past studies have shown genetic variations in genes coding for A2aRs were associated with greater sensitivity to caffeine and sleep impairment (Retey 2007), and greater anxiety after caffeine (Childs 2008). This study refines the existing model and should inspire, and lead to more accurate interpretation of, future genetics studies.*
*Other significant genes that underly individual differences in the subjective effects of caffeine include CYP1A2, or cytochrome enzyme P-450 1A2, which is associated with caffeine metabolism, and those coding for dopamine D2 receptors.
Lazarus M, Shen HY, Cherasse Y, Qu WM, Huang ZL, Bass CE, Winsky-Sommerer R, Semba K, Fredholm BB, Boison D, Hayaishi O, Urade Y, & Chen JF (2011). Arousal Effect of Caffeine Depends on Adenosine A2A Receptors in the Shell of the Nucleus Accumbens. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (27), 10067-10075 PMID: 21734299
Childs E, Hohoff C, Deckert J, Xu K, Badner J, de Wit H (2008) Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology. 33:2791– 2800
Retey JV, Adam M, Khatami R, Luhmann UF, Jung HH, Berger W, Landolt HP (2007) A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity
to caffeine effects on sleep. Clin Pharmacol Ther. 81:692–698
Speaking of the misuse of research studies for ideological purposes, check out Senator Al Franken (D-Minn) calling out apparent homophobe Tom Minnery, who represents a group of conservative christian extremists calling themselves “Focus on the Family”, during a Senate hearing on the repeal of The Defense of Marriage Act (DOMA).
In a nutshell, Minnery had misinterpreted a 2010 study by the Department of Human and Health Services in support of his conclusion that …
“… children living with their own married, biological, and/or adoptive mothers and fathers were generally happier and healthier, had better access to health care; less likely to suffer mild or severe emotional problems; did better in school; were protected from physical, emotional, sexual abuse; and almost never live in poverty compared with children in any other family form.”
Franken pointed out that he had read the study, and this is not what it said.
“I checked the study out,” said Franken, “and I would like to enter into the record, if I may, it actually doesn’t say what you said it says. It says that nuclear families — not opposite sex married families — are associated with those positive outcomes. Isn’t it true, Mr. Minnery, that a married same sex couple that has had or adopted kids would fall under the definition of a nuclear family in the study that you cite?”
Minnery responded that he thought nuclear family, as defined in the study, meant one headed by a husband and wife.
“It doesn’t,” Franklin responded. “The study defines a nuclear family as one or more children living with two parents who are married to one another and are each biological or adoptive parents to all the children in the family. And I frankly don’t really know how we can trust the rest of your testimony if you are reading studies these ways.”
There was much laughter in the chamber during the exchange.
The authors of the study confirmed (via Politico) that Franken’s interpretation of the study was correct and said the study does not provide evidence that straight couples’ children necessarily fare better than same-sex couples’ kids, as Minnery had so hopefully claimed.
Of course, this won’t change the minds of the religious nutters who go around spouting this nonsense, but it still felt good to watch nonetheless. Minnery and his colleagues should know better than to expect to find empirical evidence to support their claims. Anyhow, why should they need evidence? They’ve got their faith!