A combination of two drugs used to treat hay fever and psychosis cooled down the core body temperature of mice and monkeys, reducing brain damage after a stroke. These medications have also undergone preliminary testing in people, and will now be evaluated in a follow-up clinical trial.

Researchers have spent decades investigating ways to chill people’s brains after they have a stroke to try to limit the damage. The idea is to freeze brain cells in a hibernation-like state so they don’t need as much oxygen and glucose when a stroke cuts off their blood supply. If brain cells can be kept alive until blood flow is restored, for example, by removing a clot, a patient may be spared from extensive brain damage and related speech and movement problems.

Unfortunately, the physical cooling strategies that have been looked at so far – including cooling blankets, ice packs and helmets – haven’t worked well. This is because they cause intense discomfort and uncontrollable shivering, says at the University of Newcastle in Australia, who wasn’t involved in the study.

Shivering is one method the body uses to “fight the induction of hypothermia”, making it hard to get body temperature down low enough, she says. “It’s great to see different cooling therapies being tested out for stroke because we know that physical cooling is just not feasible,” says Coupland.

Shuaili Xu at Capital Medical University in Beijing, China, and his colleagues administered the two drugs, promethazine and chlorpromazine, which have been known to reduce body temperature , to mice and rhesus monkeys following induced strokes.

In both animals, the drug combination led to drops in core body temperature, suppressed glucose metabolism in cells and lessened the amount of brain damage caused by the stroke. The reduced brain damage also meant the treated monkeys displayed better use of their limbs.

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Next, the team conducted a clinical trial involving 32 people who had just had a stroke. Upon hospital admission, the subjects were given the promethazine and chlorpromazine combination or a placebo, in addition to standard clot-removal therapy.

The promethazine and chlorpromazine treatment only reduced the patients’ body temperature by 0.3°C (about 0.5°F) and did not reduce stroke damage. However, Xu thinks this is because the infusions were done over 12 hours, which was too slow to bring down core body temperature by a meaningful amount. “It might have led to a low blood drug concentration per unit of time,” he says.

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His team is now launching another trial to see whether faster infusions over an hour produce stronger cooling effects and therapeutic benefits. “The fact that they’ve proven that it’s safe and these drugs are already used in humans for other indications means I think that it’s reasonable to proceed with further clinical trials,” says Coupland.

Promethazine and chlorpromazine are known to be relatively safe because they have been used for decades. Promethazine is a sedating antihistamine that can ease hay fever and assist sleep, while chlorpromazine is an antipsychotic drug used in the management of schizophrenia and bipolar disorder. They both act on the central nervous system to reduce core body temperature, without translating into shivering or subjective feelings of coldness.

Too much of a good thing

Resting body temperature rises a little bit each year in women from the age of 18 to 42, for reasons that are still being figured out. The finding opens up the possibility of using temperature-sensing wearables to track ageing and detect perimenopause or potential health problems.

“We think there is a lot of information about health in the temperature signal,” says  at SRI International, a research institute headquartered in California. “We hope this facilitates investigations to identify novel markers of conditions – it may be an untapped resource of information about our health.”

Gombert-Labedens and her colleagues analysed data from a  that asked more than 750 women aged 18 to 42 to measure their oral or rectal temperature with a thermometer every day when they first woke up.

The readings showed that, on average, body temperature was lower during the first half of the participants’ menstrual cycles and higher during the second half, after ovulation occurred. Many fertility-tracking apps use this temperature jump to predict a user’s fertile window.

Gombert-Labedens and her colleagues re-examined the data in more detail to investigate the effect of age on temperature across different stages of the menstrual cycle. They found that each year from age 18 to 42, the participants became a fraction warmer, on average. As a result, those aged 35 and older tracked about 0.05°C hotter than the younger subjects across both halves of the menstrual cycle.

This is consistent with the team’s previous research that found that finger skin temperature, measured continuously by a smart ring, was  than in those aged 18 to 35.

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Further research is required to explain why this temperature increase occurs, but it probably has something to do with hormonal changes, especially towards the end of the reproductive years, says Gombert-Labedens. When perimenopause begins, temperature can increase suddenly and cause hot flushes and night sweats, but it’s unclear whether this is linked to the same mechanisms, she says.

The study only included women who did not use hormonal contraception and did not have hormonal conditions such as PMOS (polyendocrine metabolic ovarian syndrome, previously known as PCOS), so we don’t yet know how these factors might affect body temperature over time.

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Other research has found that after menopause, body temperature in women tends to  and become similar to that of men.

The higher temperature around midlife may explain why anecdotally, some women at this age say they don’t feel the cold as much as they used to, says Gombert-Labedens. “We speculate that the higher temperature in midlife women could influence their perception and reaction to environmental temperature,” she says.

As smart rings and other temperature-sensing wearables become more popular, it may be possible to identify patterns or deviations in individuals’ temperature trends that signal the approach of menopause, provide an estimate of their rate of biological ageing or detect early signs of ovarian cancer or other conidtions, says Gombert-Labedens.