Orexin

Orexin is a wakefulness-promoter in the brain. One of the deciding factors in RSR is most likely having increased orexin action, and ISR is hypothesized to follow the inverse rule (lack of orexin is known to both decrease sleep quality and inhibit wakefulness).

Role in Medicine and Sleep disorders

Insomnia is sometimes treated by administering orexin antagonists (blockers) - even though simply following RSR-specific advice can often lead to much better results.

Narcolepsy is a lack of orexin, and is sometimes treated with orexin agonists or comparable drugs like Nuvigil/Armodafinil or Modafinil.

Orexin and (Long-) COVID

COVID-19 has been linked to an autoimmune disease where one of the Orexin receptors (OX2) are attacked. It is probable that the ME/CFS that can follow COVID infections is at least in part caused by this lack of orexin receptors, with many of ME/CFS's symptoms having been linked to orexin in some way. Modafinil, for example, has even been reported to have improved PEM.

OX2 binds both orexin A and orexin B, just like OX1. Any areas of the brain which use OX2 receptors over OX1 (the distribution is not uniform) will therefore not receive orexin signaling, while signaling to OX1 would be uninhibited. This could^{[speculation]} explain RSR and ME/CFS happening at the same time, despite sounding paradoxical. In fact, said RSR might^{[speculation]} be caused by the increased orexin available to bind to OX1 (because it isn't bound by OX2 anymore).

Orexin, ADHD, and Bipolar Disorder

The Canadian Network for Mood and Anxiety Treatments (CANMAT) suggests modafinil as a second-line treatment for combinations of ADHD and bipolar disorder (after stimulants + antidepressants). It is somewhat effective at improving both ADHD and BD symptoms with little to no side effects, although usually not as effective as treating them individually.

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_{The medical sections of this article consist of own research by TudbuT/MonoGirl. They are not based on the consensus of polyphasic sleep experts, unlike most other articles on polyinfo.}