Orexin: the brain chemical that helps you stay awake

Many brain chemicals shape sleep and wakefulness. According to the US NINDS, the ones that keep some parts of the brain active while we are awake include norepinephrine and orexin — orexin is also called hypocretin. GABA, by contrast, is associated with sleep and sedation. (NINDS — Brain Basics: Understanding Sleep)

This article explains what research has shown so far; it is not a diagnosis or a treatment.

A discovery with two names

Orexins were discovered in 1998 by two independent groups of scientists. One named them after the Greek word orexis (appetite), because injecting them into the brain made animals eat; the other called them hypocretins. We now know they are the same substances. They are made only by nerve cells in one area of the hypothalamus, and their main role is now considered to be regulating sleep and wakefulness. (Inutsuka & Yamanaka, Nagoya J Med Sci 2013)

What orexin does in the brain

• According to a 2017 review in Neuron, orexins strongly excite all the brain regions that promote wakefulness, as well as the cortex. (Scammell et al., Neuron 2017)
• Orexin matters most for staying awake for long stretches. In animals its activity is high during their active period; mice that lose their orexin cells cannot stay awake for long bouts, even though their total time awake is only slightly lower. (Scammell et al., Neuron 2017)
• Orexin also suppresses REM sleep. Animals with a disrupted orexin system can switch suddenly from wakefulness into a REM-like state. (Scammell et al., Neuron 2017)
• Signals from the body clock reach orexin cells too: an area of the hypothalamus that receives output from the master clock excites them and so helps time wakefulness. (Scammell et al., Neuron 2017)
• Orexin cells are also connected to circuits for emotion, energy and reward. The authors of a 2013 review sum it up as orexin relaying information about the environment so that there is the right amount of sleep and wakefulness. Most of these findings come from animal studies. (Inutsuka & Yamanaka, Nagoya J Med Sci 2013)

What narcolepsy revealed

• In narcolepsy, the NHS says, a person is sleepy during the day, may fall asleep suddenly and sometimes has sudden muscle weakness triggered by emotions such as laughter (cataplexy). (NHS — Narcolepsy)
• Nearly all people with type 1 narcolepsy have extremely low levels of hypocretin, according to NINDS. The main cause is the loss of hypocretin cells in the hypothalamus; scientists believe the body's own immune system attacks them, but why this happens is not yet known. (NINDS — Narcolepsy)
• Mice lacking orexin, its receptor or the orexin cells have fragmented sleep similar to narcolepsy. (Inutsuka & Yamanaka, Nagoya J Med Sci 2013)
• Researchers are studying treatments that would add orexin or help it work better, NINDS says; for now this is research. (NINDS — Narcolepsy)

Orexin and sleeping pills

• Because orexin supports wakefulness, prescription medicines have been developed that block its receptors. In its 2017 guideline the American Academy of Sleep Medicine (AASM) gave the first of them only a weak recommendation, for trouble staying asleep in adults, and rated the overall quality of evidence as low. (AASM guideline, J Clin Sleep Med 2017)
• According to the AASM, the standard treatment for chronic insomnia is cognitive behavioural therapy for insomnia (CBT-I) (AASM guideline, J Clin Sleep Med 2017). GPs in the UK now rarely prescribe sleeping pills, the NHS says, because they can have serious side effects and you can become dependent on them. (NHS — Insomnia)
• Any sleeping medicine is a decision for your doctor; this article does not recommend any medicine.

When to see a doctor

• The NHS advises seeing a GP if you feel tired all the time for no reason, fall asleep suddenly during the day, or have sleep problems that worry you or affect your life. (NHS — Narcolepsy)
• If you feel sleepy, don't drive. (NHS — Insomnia)
• An AI health check is not a medical review. This article is not medical advice.

Takeaways

1. Orexin (hypocretin) is made by a small group of cells in the hypothalamus and helps the brain sustain wakefulness.
2. Above all it lets us stay awake for long stretches, and it suppresses REM sleep.
3. In type 1 narcolepsy the hypocretin cells are lost — with daytime sleepiness and sudden sleep.
4. Some sleeping pills block orexin receptors; they are prescription-only, and CBT-I remains the standard insomnia treatment.
5. Tiredness for no obvious reason or falling asleep suddenly in the day → GP.

Wakefulness is not just "sleep switched off" — the brain actively works at it, and orexin is one of its key helpers.