Researchers May Have Found a New Clue to Treating Insomnia

0 Share Newsweek is a Trust Project member See more of our trusted coverage when you search. Prefer Newsweek on Google to see more of our trusted coverage when you search. A naturally occurring molecule in the brain may play an important role in signaling when it is time to sleep, according to new research that identified a previously unrecognized mechanism involved in regulating sleep pressure.

Researchers at the Chinese Academy of Sciences and collaborating institutions found that levels of a molecule called tryptamine rise the longer animals stay awake, reflecting the growing biological need for sleep. The study, published in Nature Neuroscience , also identified a receptor called GPR139 that appears to help translate that signal into sleep-promoting activity in the brain.

The discovery centers on sleep pressure —the urge to sleep that builds during waking hours and fades after rest. Scientists have long understood that sleep pressure is a fundamental part of healthy sleep regulation, but exactly how the brain tracks that need has remained unclear.

Dr. Klar Yaggi, professor at Yale School of Medicine and director of the Yale Centers for Sleep Medicine, who was not involved in the study, told Newsweek that sleep is controlled by two separate but interconnected systems.

“Sleep is governed by two interacting systems. The homeostatic sleep drive builds during wakefulness and dissipates during sleep, while the circadian clock determines when the brain is most prepared for sleep or wakefulness,” Yaggi said.

“These systems converge on hypothalamic and brainstem circuits that switch between sleep and arousal (or wakefulness). This is often described as ‘the two-process model of sleep regulation.’”

According to Yaggi, researchers have already identified several naturally occurring substances involved in sleep regulation. Adenosine is among the best-known examples, accumulating in parts of the brain during wakefulness and promoting sleep. However, he noted that there is probably no single molecule responsible for sleep pressure.

“The new study identifies tryptamine as another candidate signal,” Yaggi said.

To investigate its role, researchers studied both nocturnal mice and diurnal pigs using a newly developed tool that allowed them to track tryptamine levels in cerebrospinal fluid throughout the sleep-wake cycle. They found that levels of the molecule increased with time spent awake and with physical activity, then dropped after sleep. Importantly, the rise was linked to how long the animals had been awake rather than the time of day.

The team also found that neurons active during wakefulness naturally released tryptamine. Once released, the molecule activated GPR139 receptors on sleep-promoting neurons in the preoptic region of the hypothalamus, increasing their activity and helping drive sleep. When researchers disrupted the pathway, the animals showed impaired rebound sleep following sleep deprivation.

Yaggi said the findings fit with the idea that the brain uses chemical signals to convert prior waking activity into a biological drive for sleep.

“Wake-active neurons released tryptamine, which activated GPR139 receptors on sleep-promoting neurons in the preoptic hypothalamus. Disrupting this pathway impaired the normal rebound after sleep deprivation,” he said.

The researchers then explored whether the newly identified pathway could be manipulated. In experiments involving both mice and pigs, compounds that activated the GPR139 receptor increased both sleep duration and sleep quality.

Those results raise the possibility that the pathway could eventually become a target for new sleep treatments.

“The most immediate opportunity is probably not administering tryptamine itself, but targeting its receptor, GPR139,” Yaggi said.

Because GPR139 belongs to a class of receptors that is commonly targeted by medicines, he said researchers may be able to develop compounds that strengthen the brain's natural sleep-pressure signal.

Still, Yaggi cautioned that translating findings from laboratory animals into treatments for people is a major challenge.

“The evidence comes from mice and pigs, predominantly under experimental sleep deprivation,” he said. “Recovery sleep in healthy animals is not the same as chronic human insomnia.”

“A practical bedtime medication must enter the brain quickly, wear off before morning, and avoid accumulation,” Yaggi said. “There is also the concern that tolerance could develop, where the effect diminishes with use over time.”

If future studies confirm that the same mechanism exists in humans, the approach could offer a fundamentally different way of treating sleep problems than existing therapies.

Traditional sedative medications generally work by broadly enhancing inhibitory GABA signaling in the brain. Other treatments act by reducing wakefulness or influencing the body's internal clock. A therapy based on the tryptamine-GPR139 pathway would take a different approach by working with what appears to be the brain's own signal that sleep is needed.

“A tryptamine–GPR139 treatment would instead activate a pathway that appears to encode the accumulated biological need for sleep, which is highly novel,” Yaggi said.

Whether that ultimately leads to better sleep treatments remains unknown. As Yaggi emphasized, any potential advantages remain theoretical.

“This could theoretically produce sleep more closely coupled to normal homeostatic mechanisms, with better preservation of slow-wave physiology and fewer nonspecific sedative effects. However, these benefits remain hypotheses.”

Huateng Cao, Kui Wang, Jin Zhao, Zhong-Hua Zha, Qian Zhang, Yijin Xiu, Bangsheng Wu, Shajin Huang, Xiao-Na Zhu, Xiaoting Li, Jianan Chen, Han Wen, Siwen Pan, Ke-Xin Yang, Ji Hu, Jin-tai Yu, Zhi-Jie Liu, Tian Hua, Yu Mu, Zhian Hu, Peng Yuan, & Zhe Zhang.

Tryptamine from wake-active monoaminergic neurons regulates sleep homeostasis, Nature Neuroscience (2026).

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