Why some People don’t Feel the Buzz of Caffeine

By Hannah Seo / The Washington Post

13:31 JST, October 14, 2023

I have never felt the effects of caffeine. I can drink coffee at 10 o’clock at night and promptly fall asleep. Following the suggestion of a caffeine researcher, I once spent a month drinking nothing but decaf, then switched back to a month of fully caffeinated beverages. Again, nothing.

It turns out, the coffee experience is not the same for everyone. How we respond to coffee, whether we like the taste and even how it influences our risk for heart attack or hypertension are all largely determined by our genes.

And it’s one gene in particular – CYP1A2 – that appears to strongly influence our body’s sensitivity to caffeine. CYP1A2, the gene, controls an enzyme, also called CYP1A2, that is responsible for breaking down caffeine and clearing it from the body. What variant of this you have can change how quickly you metabolize caffeine.

About half of all people have two copies of the CYP1A2 “fast” variant, making them ‘fast’ caffeine metabolizers. Another 40 percent have just one copy and are ‘slow’ metabolizers, and the remaining 10 percent with no copies are ‘ultraslow,’ says Ahmed El-Sohemy, a professor of nutritional sciences at the University of Toronto. El-Sohemy is founder of Nutrigenomix, which partners with health-care providers to conduct genetics-based nutrition testing.

Caffeine has an estimated half life of two to eight hours. That means, depending on your metabolism, it might take your body as little as two hours or as long as eight hours to remove half the caffeine in your system.

But the speed of your caffeine metabolism isn’t the only factor influencing how you feel when you drink coffee or caffeinated beverages.

Caffeine works by binding to adenosine receptors in the brain (which affect a person’s need for sleep), and blocking them from being activated, says Manuel Díaz-Ríos, director of the neuroscience program at Bowdoin College.

The number of these receptors in your brain is determined by both genetics and how much caffeine you routinely consume. For example, if you consistently drink a lot of coffee, and those channels are consistently blocked, the body compensates by creating more adenosine receptors. More caffeine is then needed to get the same effect, thereby increasing your caffeine tolerance.

But some people, Díaz-Ríos says, naturally start out with higher levels of certain neuroreceptors than others. And “if you’re a person who genetically just happens to produce a lot of those receptors, then you are likely to be less sensitive to caffeine” than others. These people have so many adenosine receptors that normal or even excess amounts of coffee won’t block them all.

“If you have genetic variants that allow you to metabolize caffeine more quickly, you’re more likely to consume more caffeine and possibly just tolerate a higher level,” says Marilyn Cornelis, an associate professor of preventive medicine at Northwestern University’s Feinberg School of Medicine.

Genetics can also influence preference for coffee. In a 2021 study, she found that individuals with genetic variants associated with high caffeine sensitivity were less likely to enjoy the bitter taste of dark coffee.

Sensitivity to caffeine isn’t just about whether you feel wired after drinking coffee. The genetics of caffeine sensitivity also have implications for cardiovascular health.

In a 2006 study of more than 4,000 people, researchers found that for slow metabolizers, consuming more cups of coffee per day was associated with an increased risk of a heart attack. Fast metabolizers had no such increased risks.

Slow metabolizers who drink a lot of coffee are also at higher risk of other conditions like hypertension and kidney disease. El-Sohemy says that these results imply that when caffeine lingers in the bloodstream it could cause some damage to different bodily tissues – though exactly how this happens is unclear. It may be that fast metabolizers break caffeine down quickly enough that it doesn’t cause this damage.

A person’s caffeine metabolism also influences whether caffeinated beverages give them a boost during exercise. Since caffeine is thought to be performance enhancing, researchers initially thought that slow metabolizers would benefit more because caffeine stays in their body longer. But the opposite is true.

El-Sohemy and other researchers have measured how exercise performance in fast or slow metabolizers changes after they consume caffeine. In the study, fast metabolizers were shown to cycle faster during a time trial after ingesting caffeine, while slow metabolizers post slower times after consuming the drug.

Differences in fast and slow metabolizers have also been shown in handgrip strength tests. A 2012 study of 35 male cyclists analyzed the effects of caffeine on performance and showed a similar boost in fast metabolizers.

It appears that fast metabolizers get the immediate boost from caffeine, but because their body breaks it down more quickly, the caffeine doesn’t stay in their body long enough to have negative effects. Caffeine is a vasoconstrictor that can decrease blood flow to the muscles, which is one reason it may hinder exercise performance in slow metabolizers.

If you’re curious about your CYP1A2 status, genetic testing services like 23andme can report back whether you are likely to be a fast or slow metabolizer. Other services offering genetics-based nutrition data, such as El-Sohemy’s company Nutrigenomix, can only be ordered by a health care professional. Consumer genetics testing can be “a bit like the wild west,” he says.

The effects of caffeine can vary widely from person to person. Oral contraceptives can decrease CYP1A2 activity and increase your sensitivity to caffeine, says Cornelis. Smoking increases the activity of CYP1A2, allowing smokers to metabolize caffeine more quickly, said Cornelis. Smokers who quit generally may need to cut back on coffee because they’re more sensitive to it.

And people with attention-deficit/hyperactivity disorder or ADHD can react differently to caffeine. People with ADHD often have under-stimulated brains that are not getting enough dopamine, says Sarah Karalunas, an associate professor of psychological sciences at Purdue University. Since caffeine is a stimulant that can enhance dopamine in the brain, taking it can nudge someone with ADHD out of that deficit and into a more optimal level of functioning, she says.

But caffeine can cause overstimulation in those taking ADHD medications, such as Adderall, Vyvanse or Ritalin. These drugs work by increasing dopamine and norepinephrine levels in the brain, so adding caffeine to the mix can cause side effects.