Orexin-A

Where it comes from

Made in

About 70,000 neurons of the lateral hypothalamus, which project through the whole brain

Sent out by

Wakefulness, hunger, excitement and reward; silent in sleep

Acts on

• The arousal centres (locus coeruleus, tuberomammillary nucleus, raphe)
• Reward circuits
• Feeding circuits
• Sympathetic outflow

What it does

• Holds the brain awake and stabilises the switch between sleep and waking ¹
• Drives feeding and the pursuit of reward, including drugs
• Loss of the orexin neurons, by autoimmunity, causes narcolepsy type 1 with cataplexy

In medicine

• Spinal fluid orexin-A below 110 pg/mL diagnoses narcolepsy type 1 ²
• The dual orexin receptor blockers suvorexant (2014), lemborexant and daridorexant treat insomnia by switching the wake signal down ³
• Oveporexton, an orexin-2 receptor agonist, cut sleepiness and cataplexy in two phase 3 trials and was approved in the United States in August 2026 for narcolepsy type 1 ⁴

Beyond the body’s own use

• Orexin receptor blockers are in trials for alcohol and opioid use disorder and for Alzheimer’s disease, where poor sleep speeds amyloid build-up; neither use is approved ¹
• Replacing the signal has now overtaken stimulating what is left: the orexin-2 agonists work in narcolepsy because the receptor survives after the neurons that feed it are gone ⁴
• Neither the peptide nor the agonists can be had without a prescription, and the approved blockers are controlled substances in the United States because of their sedative effect ³