Michael Greger M.D. FACLM March 27th, 2019 Volume 46
Genetic differences in caffeine metabolism may explain the Jekyll and Hyde effects of coffee.
Three-quarters of American adults drink coffee, about half of which on a daily basis. That comes out to a million tons of coffee every year. Might there be “grounds for concern”? Population studies have found that coffee drinkers tend to have lower risk of Parkinson’s, less prostate cancer (especially the women), less liver cancer, less diabetes, liver cirrhosis, depression among women, and a reduction in mortality overall, such that coffee drinkers tend to live longer than non-coffee drinkers, with mortality bottoming out at about four cups a day. But these are all just associations. You don’t know if it’s cause and effect…until you put it to the test.
For example, coffee really does seem to protect the liver. Take people with chronic hepatitis, and have them drink coffee, or not, for a month, then switch them back. And, the coffee really did seem to help. Similarly, randomize Parkinson’s patients to get two cups of coffee’s worth of caffeine, and get a significant improvement in movement symptoms within three weeks. Runners randomized to drink coffee shaved about six seconds off their mile. Weightlifters randomized to coffee can squat more weight, about 600 pounds more worth of reps. And, not just athletic performance. A cup of coffee’s worth of caffeine can significantly improve IELT, which stands for “intra-vaginal ejaculation latency time,” from two minutes all the way up to five.
Unfortunately, those effectively randomized at birth to genetically just have a higher predilection to drink coffee do not appear to be protected from diabetes, or depression, or Alzheimer’s, or obesity, or metabolic syndrome. So, it seems the protective associations may just be due to “confounding factors,” like, maybe those who drink coffee just happen to exercise more, or something. And, the same with prostate cancer—no apparent cause-and-effect relationship, and even the mortality benefit seemed to disappear.
Even if a study did show coffee drinking could extend lifespan by reducing inflammation, or improving lung function or insulin sensitivity, that would mean on average. There is “interindividual variability…after consumption of major plant-food…compounds,” meaning people may respond differently. For example, how crazy is this? “In some [rare] individuals,…heavy use of caffeine apparently provokes sleepiness.” That’s an extreme example. Most of the time, it’s just that “some individuals may benefit more than others from the health effects of [different foods].” For example, because of differences in gut bacteria, only a minority of Westerners may derive extra benefit from soy, as I’ve described before. The most common difference in caffeine effects is that while most people metabolize caffeine rapidly, certain gene variants in liver detox enzymes make some people slow metabolizers. Might that make a difference?
Well, habitual coffee consumption of at least three cups a day has been “associated with uncontrolled [blood pressure]” among older individuals diagnosed with hypertension, suggesting that “moderating coffee intake” may be a good idea for some people. But, even if it was cause-and-effect, that would be on average. What would happen if you split people up by how fast they metabolize caffeine? Compared to coffee abstainers, those who have impaired caffeine metabolism genes have an elevated risk of becoming hypertensive at one to three cups a day, and especially at four or more. Okay, but check this out. For the rapid metabolizers, not only was there no excess risk at one to three cups, heavy coffee drinkers were protected, meaning apparently the more coffee they drank, the lower their risk. How do we explain that?
“Coffee is a complex ‘blend’ of a vast number of different [compounds].” There are protective polyphenol antioxidants that are beneficial. Coffee beans are, after all, beans; well, actually, seeds—but seeds are really healthy too! On the other hand, there’s the caffeine, which can spike adrenaline levels in the blood—but only if you’re a slow metabolizer. Rapid metabolizers can clear caffeine so fast that there’s no increase in adrenaline even at four or more cups a day. And so, then you just have the beneficial polyphenols that actually lower your blood pressure—hence the benefit overall. “Thus, there seems to be a Jekyll and Hyde aspect to coffee, whose overall action on the cardiovascular system appears to be regulated by” that gene for the enzyme that metabolizes caffeine.
“The important question,” though is, “Does it give women larger breasts?” W-w-hat?! Young women who drink a lot of coffee and are rapid caffeine metabolizers have about a half-a-baseball-sized larger breast volume, which may be a bad thing, “as breast volume is associated with breast cancer risk.” But no, the important question is, “What about heart attack risk?” In slow metabolizers, daily coffee consumption appeared to double the odds of a heart attack, or even quadruple the odds at four cups a day, whereas in the rapid caffeine metabolizers, daily coffee consumption was protective, cutting the odds of heart attack by more than half—or at least until you get up to four or more cups a day. “The protective effects observed among rapid metabolizers suggest that the efficient elimination of caffeine might have unmasked the protective effects of other [phyto]chemicals in coffee.”
We think it may be the adrenaline again, since if you’re a slow metabolizer of adrenaline, high coffee consumption may put you at risk as well.
So, is coffee “friend or foe”? “[T]hese studies suggest the possibility that slow caffeine metabolizers who consume caffeinated coffee may have an increased risk of [cardiovascular disease], whereas fast caffeine metabolizers may be protected from this risk by the antioxidants and other beneficial compounds present.”
