Cooling the brain is one of the most powerful neuroprotective strategies known to medicine. Lowering brain temperature by just a few degrees slows metabolism, reduces oxygen demand, and dampens the inflammatory cascades that cause secondary damage after stroke or traumatic brain injury. The problem has never been whether hypothermia works — it is how to achieve it without causing more harm than good.
Physical cooling methods — ice packs, cooling blankets, helmets, chilled intravenous fluids — have been tried for decades. They trigger intense shivering, which generates heat and fights the cooling effect. Patients find them deeply uncomfortable, often requiring sedation or paralyzing drugs to tolerate them. Shivering is the body’s natural defense against hypothermia, and it is remarkably effective at thwarting attempts at therapeutic cooling.
Two recent lines of research offer different solutions to this problem: one pharmacological, one neurological. Both aim to induce hypothermia from the inside rather than the outside.
A team led by Dr. Shuaili Xu has been testing a combination of two inexpensive, decades-old drugs — promethazine, an antihistamine used for hay fever and sleep, and chlorpromazine, an antipsychotic used for schizophrenia — for their ability to lower core body temperature. Both act on the central nervous system to suppress the body’s thermoregulatory drive, reducing temperature without triggering the shivering reflex.
In mice and rhesus monkeys, the drug combination produced a measurable drop in core body temperature and suppressed glucose metabolism in brain cells. In animals with experimentally induced strokes, the treated group showed less brain damage, and monkeys demonstrated improved limb use during recovery.
“We know that physical cooling strategies haven’t worked well because they cause intense discomfort and uncontrollable shivering,” said Dr. Kirsten Coupland of the University of Newcastle, Australia, who was not involved in the study. “It’s great to see different cooling therapies being tested for stroke.”
A phase I/II clinical trial tested the approach in 32 people who had just suffered a stroke. Participants received either the drug combination or a placebo alongside standard clot-removal therapy. The result was modest: a temperature drop of only 0.3 degrees Celsius, and no measurable reduction in stroke damage. The researchers suspect the problem was not the drugs but the delivery — the infusion was given over 12 hours, too slow to achieve a meaningful concentration. A new trial is planned with infusions delivered over one hour.
The advantage of this approach is clear: both drugs are already approved by the FDA, have been in clinical use for decades, and have well-characterized safety profiles. “The fact that they’ve proven it’s safe, and these drugs are already used in humans for other indications, means it’s reasonable to proceed with further clinical trials,” Coupland said.
The findings were published in Science Translational Medicine.
Cooling From the Brain Itself
A second, entirely different approach takes advantage of the brain’s own thermoregulatory circuitry. In 2023, researchers at the University of Tsukuba in Japan discovered that a specific population of neurons in the hypothalamus — which they named Q neurons — acts as a master switch for body temperature. When chemically stimulated, these neurons induce a deep, hibernation-like hypothermic state in mice, dropping core body temperature without any external cooling.
The method, called QIH (Q neuron-induced hypothermic/hypometabolic state), was developed by Professor Takeshi Sakurai and his team at the university’s International Institute for Integrative Sleep Medicine.
In a study published in the Journal of Neuroscience in September 2025, the Tsukuba team applied QIH to a mouse model of mild traumatic brain injury. The results were striking: sustained reductions in core body temperature significantly attenuated the hyperactivation of microglia and astrocytes — the brain’s inflammatory cells — which normally drive secondary damage after injury. Treated mice showed preserved neuronal integrity, reduced neuroinflammation, and accelerated recovery of motor function.
The key advantage of QIH is that it works through the brain’s natural thermoregulatory system rather than fighting it. Conventional hypothermia methods suppress shivering with paralyzing drugs but leave the body’s heat-generating systems still trying to raise temperature. QIH, by contrast, resets the thermostat from within.
“Unlike traditional hypothermia, QIH avoids external cooling, offering a potentially safer and more practical approach to TBI treatment,” the authors wrote.
A Common Goal
The two approaches remain at different stages of development. The drug combination has cleared early human safety testing and is moving toward a more aggressive clinical trial. QIH is still in the preclinical phase, with studies so far limited to mice. Both face the same fundamental challenge: whether cooling from the inside, whether pharmacological or neurological, can achieve the depth and duration of hypothermia needed to make a clinical difference.
But both also share a conceptual shift that may ultimately make therapeutic hypothermia practical. Instead of trying to cool the brain from the outside against the body’s will, they work with the body’s own systems — by dampening the drive to shiver pharmacologically, or by directly commanding the brain to turn down its own thermostat.
Sources: (1) Xu S, et al. Drug-induced hypothermia for stroke neuroprotection. Sci. Transl. Med. 2026;18(789):eady7847. DOI: 10.1126/scitranslmed.ady7847. (2) Sakurai T, et al. Q Neuron-Induced Hypothermia Promotes Functional Recovery and Suppresses Neuroinflammation After Brain Injury. J. Neurosci. 2025;45(47):e1035252025. DOI: 10.1523/JNEUROSCI.1035-25.2025. (3) Klein A. Chilling the body with drugs could limit brain damage from stroke. New Scientist. 17 June 2026. (4) EurekAlert. Hibernation-like hypothermia suppresses neuroinflammation after brain injury. University of Tsukuba. 24 October 2025.