There Might Be a Better Time to Pop That Pill

Syncing cures with circadian rhythms is an idea whose moment has finally come.

The author of a major medical textbook was the first to observe that asthma follows a daily rhythm. The disease is worst at night, he wrote; so is tooth pain. The author was writing in Latin, because it was the fifth century.

It was an early hint that medicine might work best if we put it on a schedule. But it’s only now that timing treatments—a concept called chronotherapy—is finally on the verge of becoming commonplace. Soon your doctor might tell you to take a pill at a certain time of day because that’s when it will work best.

“There’s a tremendous amount of disorders and diseases that are more prominent in the morning or the evening,” says Barbara Canlon, a professor at the Karolinska Institute in Sweden and author of a recent review of chronotherapy called “Medicine in the Fourth Dimension.” Heart attacks are more common in the morning, and heart surgery is less risky in the afternoon. Migraines, pain from rheumatoid arthritis, and infant deaths from SIDS are also more common in the morning. Sudden death from type 1 diabetes almost always occurs at night. 

These phenomena likely occur because of circadian rhythms, the 24-hour cycles inside our bodies that scientists have been decoding over the past few decades. A 2017 Nobel Prize went to three scientists who made key discoveries about the molecular basis of these rhythms. They and others have found that a master timer in the brain uses sunlight and other cues to sync up clock-like mechanisms throughout our tissues and organs. Molecular concentrations within our bodies rise and fall every day like the sun.

That explains why taking drugs at certain times might make them work better. One telling example is a chemotherapy drug called oxaliplatin. It failed initial clinical trials for being too toxic, but further research in the early 1990s showed that when the drug was given on a continuous 24-hour cycle peaking at 4 p.m., it worked safely. Oxaliplatin is now a major treatment for colorectal cancer.

Other such cases are likely waiting to be discovered. A 2014 study found that 43 percent of genes in mice have activity that oscillates over the day. Most of this gene activity peaks either in the morning or the evening. Gene activity has daily rhythms in humans too. When the authors of the 2014 study looked at the 100 best-selling drugs in the United States, they found that 56 target a molecule in the body that cycles daily. But nearly half of those drugs decay quickly—meaning that if we take them at the wrong time of day, they might be less effective at hitting their targets. 

On the other hand, if we can find just the right time to take them, they might work better than ever.

Lagging behind

Despite the evidence that the timing of medicines matters, “Pharmaceutical companies do not take the time of the day into consideration when they’re developing their drugs or testing their drugs,” Canlon says. 

One reason may be the cost: A scientific study that takes time of day into account is more expensive than one that doesn’t. Researchers may have to collect much more data per subject—say, taking blood six times a day instead of once—and they may have to include many more groups of subjects in one study.

Funding isn’t the only challenge in circadian experiments. Much research happens in mice—which, as nocturnal animals, have a circadian rhythm opposite our own. A drug that seems promising in mouse studies done by day, when mice are normally sleeping (but scientists are awake and working), might have disappointing results when human subjects take it in the daytime. 

Another problem with rodent work is that, as Robert Dallmann puts it, “Our mice are exquisitely the same.” Dallmann is a circadian biologist working on chronotherapy at the University of Warwick in the United Kingdom. Within one medical experiment, researchers will use mice of just one strain, which are so inbred that they’re as genetically alike as clones. People, of course, have lots of differences in their DNA.

Some of those genetic differences contribute to our own unique clocks. Certain people are early birds; others are night owls. Finding that a drug works best three hours after mice wake up wouldn’t necessarily mean the same thing for every human. Intriguingly, researchers have come up with a blood test that measures the activity of a set of genes to assess where any given individual is in their body’s personal 24-hour cycle. 

However, to make more advances in chronotherapy, we may not always need to understand the complex molecular gears inside our biological clocks, says Satchin Panda, a professor at the Salk Institute in California and author of the book The Circadian Code. For example, past research has shown that high overnight blood pressure puts people at especially great risk of heart attacks and strokes. A recent large study showed that no matter what blood-pressure medication people are taking—even though those drugs target different molecules within the body—taking the medication at bedtime protects patients better from heart disease and death. 

Researchers can reach this conclusion without spending the money to learn the exact circadian mechanisms behind it. “It’s kind of a common-sense approach for drug timing,” Panda says. His own research group created an app called My Circadian Clock to crowdsource data from thousands of people on their habits, health, and medications. They’ll try to find links between the timing of people’s behaviors—including drug timing—and health outcomes. “Just employing what is already known on a wider scale would have quite a positive impact,” Dallmann adds.

To treat arthritis pain that’s worst in the morning, patients can now take slow-release pain medications at bedtime. And while no one wants to set an alarm for 3 a.m. to take their medication, programmable chemotherapy pumps now allow patients to get some drugs delivered at very precise times, even at home.

Although many doctors aren’t used to the idea yet, chronotherapy is getting closer to reality for more patients, Panda says. “It just takes time.”

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