Genetic differences in caffeine metabolism may explain the Jekyll and Hyde effects of coffee.

Three-quarters of American adults drink coffee and about half do so on a daily basis. That comes out to a million tons of coffee every year. Might there be “grounds for concern?” I look at the differential benefits of coffee consumption in my video Friday Favorites: Do the Health Benefits of Coffee Apply to Everyone?.

Population studies have found that coffee drinkers tend to have a lower risk of Parkinson’s; less prostate cancer, liver cancer, diabetes, liver cirrhosis, and 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, as you can see in the graph below and at 0:42 in my video. But these are all just associations. You don’t know if it’s cause and effect until you put it to the test. 

Coffee seems to protect the liver, for example. In a study, individuals with chronic hepatitis drank coffee for a month—or didn’t—and then switched. The researchers found that the coffee really did seem to help. Similarly, Parkinson’s patients were randomized to get two cups of coffee’s worth of caffeine and showed significant improvement in movement symptoms within three weeks, as you can see in the graph below and at 1:14 in my video. Runners randomized to drink coffee shaved off about six seconds from their mile. Weightlifters randomized to drink coffee can squat more weight, about 600 more pounds’ worth of reps. This doesn’t only apply to athletic performance either: A cup of coffee’s worth of caffeine can significantly improve IELT, which stands for “intravaginal ejaculation latency time,” from two minutes all the way up to five. 

Unfortunately, those effectively randomized at birth to genetically have a higher predilection for drinking coffee do not appear to be protected from diabetes, depression, Alzheimer’s, obesity, or metabolic syndrome, so it seems the protective associations may be due to confounding factors. Maybe those who drink coffee happen to exercise more, for instance. The same with prostate cancer: There was no apparent cause-and-effect relationship, and even the mortality benefit seemed to disappear.  

Even if a study did show that drinking coffee could extend lifespan by reducing inflammation or improving lung function or insulin sensitivity, that would mean on average. There is “interindividual variability” after the consumption of “major plant-food compounds,” meaning that people may respond differently to them. For example, in some rare individuals, heavy caffeine use 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. Because of differences in gut bacteria, for instance, only a minority of Westerners may derive extra benefits from soy, as I’ve described before in my video How to Convert Into an Equol Producer. 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? 

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 were cause-and-effect, it would be on average. What would happen if you divided by how fast they metabolize caffeine? As you can see in the graph below and at 3:54 in my video, compared with 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. For the rapid metabolizers, not only was there no excess risk at one to three cups, but heavy coffee drinkers were protected, meaning that 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 bioactive chemicals,” and there are protective polyphenol antioxidants that are beneficial. Coffee beans are, after all, beans. (They’re actually seeds, but seeds are healthful, too!) However, caffeine 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, so then all that’s left are the beneficial polyphenols that lower 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 the CYP1A2 gene,” that gene for the enzyme that metabolizes caffeine. 

Researchers asked: Does it give women larger breasts? Young women who drink a lot of coffee and are rapid caffeine metabolizers have larger breast volume, about a half a baseball’s worth, which may be a bad thing because breast volume is associated with breast cancer risk. What about heart attack risk? As you can see in the graph below and at 5:42 in my video, 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—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 chemicals in coffee.” We think it may be the adrenaline again, because if you’re a slow metabolizer of adrenaline, high coffee consumption may put you at risk as well, as you can see in the graph below and at 6:17 in my video. 

So, is coffee a “friend or foe?” “Together, these studies suggest the possibility that slow caffeine metabolizers who consume caffeinated coffee may have an increased risk of CVD [cardiovascular disease], whereas fast caffeine metabolizers may be protected from this risk by the antioxidants and other beneficial compounds present.” 

This is one of the rare instances where “personalized nutrition” isn’t just a marketing catchphrase. Soy is another, but in that case, it’s about who benefits the most. See How to Convert Into an Equol Producer.

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