Your doctor tells you how many times a day you should take a pill, and whether to take it with or without food – but they very rarely tell you the exact time at which it has to be taken. Chronopharmacology (also known as chronotherapy or circadian medicine) – the idea that a pill popped at exactly the right time has maximum benefit – could be a major influence on the future of medicine. Increasing studies are showing that what time of day we treat disease can be crucial, and that it’s possible to pinpoint the time of day when certain disease is at its worst.
In 1997, doctors in Denver split 59 asthmatics into three groups. The first group used steroid inhalers at 8am every day for four weeks. The second used the same inhalers, but much later in the day, at 5.30pm. The third group dosed four times a day at 7am, 12 noon, 7pm and 10pm – at the time, this was believed to be the optimal regime.
After a month, the results were in. The 8am group saw the least improvement, while an inhaler at 5.30pm had similar efficacy to one used at regular intervals. In short, taking a drug once was just as effective as taking it four times, provided you took it at the right time of day.
Professor David Ray of the University of Oxford uses his own inhaler “at the time when I think it’s going to be most effective” (the exact time is his secret, as “we have to be careful” about single-person anecdotes). As co-director of the Sir Jules Thorn Sleep and Circadian Neuroscience Institute, the asthmatic professor has conducted his own research into body clocks and the respiratory disease. He also studies how matching medications with our circadian rhythms can improve the effectiveness of drugs.
Chronopharmacology is a field filled with jaw-dropping studies to whip out at the pub: in 2011, researchers at the University of Birmingham monitored people who had their influenza jabs in the morning versus those who had them in the afternoon. One month on, the patients who received their vaccination between 9am and 11am had higher levels of anti-flu antibodies than patients jabbed between 3pm and 5pm.
Our circadian rhythms are 24-hour cycles of biological activity that are regulated by our internal clocks along with external cues, such as light. You sleep at night not just because your mum told you to, but because when your retina detects light it inhibits the production of the hormone melatonin, stimulating wakefulness. Our body temperature varies by as much as half a degree throughout the day: usually, we’re coldest at 4am and hottest just in time for the News at Six. Our hormones, immune cells, and organ functions also fluctuate; mouse livers, for example, grow almost 50% in size during the day before shrinking at night.
Many chronobiologists (“chrono” is the Greek word for “time”) believe we should use this information to improve medical interventions. Chronotherapy is an unusual field with both a long and short history. On the one hand, way back in 1698, English physician Sir John Floyer noticed that he had asthmatic fits after sleeping and, therefore, “by late sitting up I have put by the fit for a night or two”.
There are also a number of decades-old groundbreaking studies: the Denver asthma report for one, as well as research undertaken in Canada between 1976 and 1991, which found that children given chemotherapy for their leukaemia in the evening had better disease-free survival rates than those treated in the morning. In some areas, timed medicine is already happening, for instance, many doctors prescribe certain statins – drugs for high cholesterol – to be taken at night to correspond with the time when your body produces the most cholesterol.
But there is still caution. According to Robert Dallmann, a circadian biologist and biomedical sciences professor at the University of Warwick, the field is in many ways still emerging. “There was, for a long time, a feeling that this was all much too complicated,” he says. While Floyer might have noticed his asthma worsening at night, he wasn’t equipped to know why. “Notice was only really taken once the field started to get to the molecular mechanisms underlying lots of this, because before it was mostly a black box,” Dallmann says.
In 2017, the Nobel prize in Physiology or Medicine was awarded to three American geneticists who had discovered the molecular mechanisms controlling our biological clocks. In layperson’s terms: the scientists had isolated a gene that controls the biological rhythms of fruit flies and found that this gene encodes a protein that accumulates within cells at night and degrades during the day. “I think the nominators could see all this exciting science and see that it hadn’t really translated into the clinic,” says Ray. “We are in a quite exciting time now where there’s a lot of early-phase work showing what massive potential there is here.”
Potential, of course, has pitfalls. If scientists discovered that flu vaccinations are more effective in the morning over a decade ago, then why isn’t everyone being jabbed at 9am? Well, first, that would mean the NHS could only issue half as many jabs in a week. Second, it can be hard enough getting people to attend their immunisation appointments at all; limiting them to a narrow window could mean that pregnant women with morning sickness miss their appointment, for example, which is far worse than simply being jabbed in the afternoon. There’s also the fact, Ray says, “that health systems are bureaucratic, they’re under financial pressure. It’s like a supertanker trying to change course.”
And, of course, healthcare providers don’t want to jump the gun before enough evidence has accumulated. One 2021 study of 63 healthcare workers in China found that Covid-19 vaccines were more effective when given in the morning. Later that year, a study monitoring 2,190 healthcare workers in the UK found that Covid vaccinations had better efficacy in the afternoon. The vaccinations in both studies were different, but a number of other factors complicate analysis of the results; for example, neither factored in participants’ medication history or sleep and shift-work patterns.
Then there’s the matter of funding. For pharmaceutical companies, there are marketing and safety issues when it comes to producing drugs that should be taken at an exact time of day. What are the risks if someone takes it early or late? Already, approximately 30-50% patients with long-term conditions don’t adhere to their medication. But even without new medicine, chronopharmacology can be revolutionary: Ray says the field could “rescue” drugs that have previously failed clinical trials.
It’s not uncommon for a drug to be groundbreaking in mice and ineffective in human trials. But in 2020, researchers from Harvard Medical School published a study which found that preventive stroke strategies that had worked in rodents but failed in humans may have done so because rats are nocturnal. Many trials test rats in the daytime, when they’re inactive, and test humans during the day, when they’re active and awake.
“They were able to show that a lot of these promising drugs have probably been tested in humans at the wrong time of day,” Ray says. “That’s millions and millions and millions of pounds wasted and all those volunteers recruited and subjected to a trial.” The time of day a drug is administered could also change its side-effects, so drugs that were written off as too toxic could actually be safe within certain parameters. To save money and save lives, Ray argues that many trials should have “clock logic” embedded into them.
Let’s say you need to take a drug at 8am for it to be effective, and for whatever reason – needy kids, a hangover, a fundamental disdain for the morning – you can’t. Theoretically, says University of Oxford pharmacology professor Sridhar Vasudevan, you could take one drug to change the timing of another – problem solved. Chronopharmacology isn’t just about matching medicines with your circadian rhythms: it’s also about creating medicine that affects the circadian system itself.
Vasudevan became interested in circadian rhythms when he worked in psychiatry more than a decade ago. He noticed that sleep disturbance was prevalent “across the board” in depression, bipolar disorder and schizophrenia. “When something goes wrong in the brain that leads to a mood dysfunction, you have associated sleep dysfunction,” he says. So, Vasudevan theorised, “If you can correct the sleep and circadian dysfunction, you can fix the other side, which is the mood.”
In 2016, Vasudevan co-founded a company in the Oxford Centre for Innovation, named Circadian Therapeutics. He and his colleagues are identifying drugs to treat diseases related to circadian rhythm disorders. The team are currently working with blind veterans who have disrupted sleep cycles because light cannot reset their circadian rhythms. “Basically, they’re constantly jet-legged every single day,” Vasudevan says. “The idea is to have a drug that can mimic the effects of light on the brain, so that they can take it once a day and stabilise their sense of time.”
Circadian Therapeutics are also developing drugs to help those with neurodegenerative disorders. “Sundowning” is a phenomenon whereby some people with Alzheimer’s and Parkinson’s become distressed and confused in the late afternoon. Vasudevan is looking into circadian modulators that could manage these symptoms.
Of course we shouldn’t just manipulate our body clocks for the sake of it, as Vasudevan warns that taking one newly discovered drug to affect the timing of another could “introduce extra risk”. Still, there’s potential. “If the ideal time for you to take a drug is between 1am and 4am, most people are not going to wake up to take it,” Vasudevan says, “and sleep is extremely important in the healing process, regardless of what you’re recovering from.” In some circumstances – at some point in the future – taking one drug to change your circadian timing could help another drug work better.
Drugs are not the only route to a healthy life. Chrono-nutrition and chrono-exercise are exactly what they sound like. In October 2021, a study from Harvard Medical School found that eating earlier affects the speed at which you burn calories and store fat – in short, the exact same meal could be far healthier eaten at 5pm than 9pm. In May, academics from Skidmore College in New York found that women who exercised in the morning burned more abdominal fat and reduced their blood pressure more than women who exercised in the evening – but, the later exercisers had “enhanced muscular performance”.
Before you start swallowing 10am pills and going on 3pm jogs, it’s important to remember that our internal circadian biology does vary: some of us are morning people and some of us are evening people (this characteristic is known as a chronotype). Ray says your chronotype is affected by your age, gender and genes, and argues that in the future we’ll likely see personalised chronopharmacology based on “the clock phase of the person, rather than just going off the time on the clock on the wall”.
Dallmann, who runs the Patho-Physiological Molecular Clocks Lab at Warwick University, has already used his research to work out what personally works for him. “I do implement some of the current knowledge on time-restricted eating,” he says, “and I choose my painkillers differently by time of day.”
Still, it’s important to remember that for many medicines, the time of day they’re taken doesn’t matter at all. As Ray says: “If the disease you are targeting doesn’t change by time of day then it doesn’t matter what time of day you give the drug.” If a drug has a long half-life (ie it takes weeks for the substance to reduce by half in your body), then the time of day it’s taken doesn’t matter, because its concentration remains consistent.
Sceptical scientists have also warned about being too enthusiastic. University of North Carolina biochemist Aziz Sancar has argued that when it comes to cancer, chrono-chemotherapy researchers have overstated positive findings and generalised from small studies in the past. But for now and for many, chronopharmacology remains emerging and exciting. “We have to be careful about overselling it. It can lead to dissatisfaction if you cry wolf,” says Ray. However, “We’re at that point where it’s exciting,” and people are increasingly aware of the field.
“We’ve done focus groups with patients,” Ray says, “and as soon as you say: ‘We’d really like to hear your views about timing and how the time of day affects your disease,’ they’re over the moon – because, finally, someone is listening.”