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Hypothermia is usually a medical emergency. But under the right conditions, controlled cooling can also be a way to protect the brain, including after a stroke.

Researchers have long wondered whether lowering body temperature could limit the damage caused by stroke. Now, a new study suggests that two decades-old medicines may help do this from the inside out.

The drugs, chlorpromazine and promethazine, can push the body into a cooler, slower-burning state that resembles hibernation. In mice and rhesus monkeys, the treatment reduced brain injury after stroke. In a small trial of 32 stroke patients, the highest dose appeared safe and, at the highest dose, produced a modest, short-lived drop in body temperature along with metabolic changes in blood tests.

Cooling Without the Ice

Doctors already know that cooling the body can sometimes protect the brain. After cardiac arrest, lowering body temperature can reduce damage in certain patients. But cooling an awake person with ice packs or cooling blankets creates a problem: the body fights back against the cold.

In practice, people shiver, which makes their muscles burn energy. Their stress responses also rise, and this can make it harder for the body to tolerate other treatments.

The new approach tries to avoid that fight. Instead of forcing heat out of the body from the outside, the drug pair seems to change how the body handles heat and fuel from within.

Chlorpromazine, an older antipsychotic, and promethazine, a long-used antihistamine and sedative, have both been around for decades. Together, the researchers call them C+P because they’re often used in tandem.

In mice, the combination lowered body temperature and slowed metabolism without the tremors seen during surface cooling. The animals used less oxygen and shifted away from sugar-burning toward fat-based fuel use—a pattern the researchers compared with torpor, the low-energy state some animals enter to survive harsh conditions.

Then came the real test: a stroke.

Researchers blocked a brain artery in mice to mimic an acute ischemic stroke, the most common kind of stroke, caused by a clot cutting off blood flow. Mice treated with C+P had smaller damaged areas in the brain and better neurological scores 24 hours later. Brain scans also showed less lactate buildup, a sign of reduced chemical stress in injured tissue.

From Mice to Monkeys to Patients

Promising mouse studies often fall apart on the way to human medicine. Larger bodies shed heat differently. A drug that cools a mouse may barely move the temperature of a primate.

So the team next tested C+P in rhesus monkeys. The drugs lowered core temperature to about 33 to 34 degrees Celsius, or 91.4 to 93.2 degrees Fahrenheit. Blood markers showed a shift away from glucose metabolism and toward fats and ketones. In monkeys with stroke-like artery blockages, treated animals had smaller brain injuries at 24 hours and 30 days. They also performed better on movement tasks using the affected limb.

The human trial was designed mainly to test whether this is safe enough to keep studying?

From October to December 2024, researchers enrolled 32 patients with acute ischemic stroke. All received standard clot-clearing care, either endovascular thrombectomy or clot-busting medicine plus thrombectomy. Patients then received placebo or C+P at doses of 10, 20, 50 or 100 milligrams.

The treatment didn’t cause severe low blood pressure, slowed breathing, or abnormal sedation in the trial. Two deaths occurred (one in the placebo group and one in the 20-milligram group) but this did not appear to be caused by C+P.

Only the 100-milligram dose clearly cooled patients, and the effect was small: about one-third of a degree Celsius four hours after treatment. Still, blood tests suggested that the same dose reduced markers tied to aerobic respiration and glucose metabolism.

The recovery signals were intriguing but far from definitive. At 90 days, all six patients in the 100-milligram group had favorable outcomes, compared with half of the placebo group. But the trial was too small to prove that the drug improved recovery. The difference did not reach statistical significance.

The Big Caution Macrophotography of Vespula germanica, found in a niche inside a fallen tree. Hibernating, she waits for spring to awaken and establish a new insect colony. Credit: Wikimedia Commons

The study gives scientists a plausible bridge from animal biology to human emergency care. But it also leaves major questions.

The trial involved only 32 patients at a single center. Doctors measured patients’ underarm temperature, not core temperature, making the human cooling effect harder to compare with the animal results. And blood markers may not perfectly reflect what happens inside the human brain after stroke.

For now, C+P is more of a candidate for larger Phase 2 trials.

After a stroke, saving the brain may require more than reopening a blocked artery. It may require slowing the brain’s chemistry long enough for rescue to work.

The study was published in the journal Science Translational Medicine.