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The Best of Times, the Worst of TimesWhen during the day should you take your medication? Good question.

By Emily Anthes
Posted Thursday, Nov. 1, 2007, at 11:13 AM ET
Chronobiologist Franz Halberg

It takes more than $800 million and 10 years to develop a new drug. Researchers perform study after study, testing a potential new medicine in cell cultures, animals, and humans. They determine whether it treats the right problem safely; should be taken orally, nasally, intravenously, or intramuscularly; and set minimum and maximum doses. But most drug trials ignore a question that increasingly seems crucial: When is the best time of day to take a given medication?

Modern drug development generally assumes that the body maintains a stable internal state. To that end, many prescription drugs are designed to be taken in equal amounts at regular intervals to keep a patient's drug levels steady. The problem is that a growing body of research suggests that our bodies are not constant. Instead, nearly every physiological process oscillates with our internal circadian rhythms. The body's temperature, immune function, and hormone levels all partly depend on whether it's night or day, or sometime in between. Meanwhile, many diseases also have daily rhythms, with symptoms more severe at certain times.

The body's sensitivity to time of day means that a drug proven safe to take in the morning may not be safe at night, or that a dose that works at 8 p.m. may be too small at 8 a.m. Some of the first—and still most compelling—evidence for these time-related differences came from Franz Halberg, widely considered to be the father of chronobiology. In a 1959 experiment that became a classic in the field, Halberg showed that it was easier for mice to survive a toxic dose of ethanol at one time of day than at another. Since then, time of day has proven to be an important factor in the safety and effectiveness of drugs for asthma, high blood pressure, and other conditions. These principles even apply to run-of-the-mill pills like aspirin, which does less damage to the stomach lining when taken in the evening than in the morning. (Conveniently, aspirin is also better at reducing blood pressure when taken before bed.)

Despite this evidence of variation, drug research is almost always done during daylight hours, when the humans leading the studies are awake and alert. And in the animal testing stage, it's almost always done with mice and rats, which are nocturnal—the middle of our day is the middle of their night. This can lead to gross misestimations of the effectiveness and toxicity of a drug intended for humans. "How much time, effort and money have been wasted in this way we shall probably never know," chronobiologist Josephine Arendt wrote in her 1998 overview of biological rhythms and medicine.

Things do get better, chronobiologically speaking, when drugs are eventually tested in humans, but only slightly so. The FDA requires three phases of clinical trials in humans before a new medicine can go on the market, but it does not require the testing of new compounds at multiple times of day. Instead, most clinical trials control for time of day. Which means that rather than assessing whether the effects of an experimental drug vary over the course of a day, the trials ensure that all patients take the drug in lockstep. When a drug is finally approved, the prescribing information issued by the FDA either contains no recommendation for what time of day patients should take it or directs patients to take it at whatever time was chosen for clinical trials, says Michael Smolensky, a chronobiologist at the University of Texas Health Sciences Center in Houston. And then, once the drug is on the market, a patient may decide to take a once-a-day drug at night, instead of in the morning, when it was tested—and experience side effects that neither the FDA nor the pharmaceutical companies anticipated.

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Emily Anthes is a science writer who lives in Brooklyn, N.Y.
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