Histamine is critical for maintaining arousal and wakefulness. The sole source of histamine in the brain is a region called the TMN (tuberomammillary nucleus) in the posterior hypothalamus. The hypothalamus is also where orexin comes from in the brain. Like orexin, neurons which make histamine (called histaminergic neurons) have far-reaching projections in the brain. Because of this, again, like orexin, these neurons are implicated in many different physiological states including sleep-wake control, learning, emotional status, and memory formation.
Most of us have experienced the histamine wakefulness-promoting effect when we have taken anti-histamines (Benadryl, etc.). The #1 side effect that most people notice is drowsiness. This is due to the fact that anti-histamines bind and antagonize histamine receptors (H1 receptors). Anti-histamines block histamine signaling in the brain.
In health, histominergic neuron activity is highest during wakefulness, and is becomes nearly undetectable during sleep (REM and NREM).
It has been shown previously that people with narcolepsy have low CSF histamine. In addition, the lower the corresponding orexin levels, the lower the histamine levels; indicating that proper orexin signaling in the brain is crucial for proper histaminergic signaling. The same trend has been shown for those with idiopathic hypersomnia.
Mouse models have also demonstarted a link between histamine and sleep impairment. Histamine deficient (HDC KO) mice display sleep fragmentation and increased REM sleep during the light period along with profound wakefulness deficit at dark onset, a condition that sounds intriguingingly similar to narcolepsy. Moreover, sex differences in histamine deficiency have been demonstated in mice: female HDC KO mice demonstrated “hypoactivity, increased measures of anxiety, impairments in water-maze performance, but enhanced passive avoidance memory retention.”
Currently, it has been hypothesized that histaminergic neuron activity of the TMN may be reduced in individuals with narcolepsy.
Histamine has also been implicated in neurogenesis. I’ve already discussed this concept to some degree here (although I should point out that was discussing a different region of adult neurogenesis). This has been demonstrated largely in the subventricular zone (SVZ), which is a known area of adult neurogenesis and has implications for repair following injury. The image below shows the respective regions (SVZ) in relation to the hypothalamus (where orexin neurons are).

Thanks for these excellent posts! Its hard to find well researched information on alternative treatments for narcolepsy so your work here is greatly appriciated. I am managing well on Xyrem but hate that my quality of life is drug dependent. I am “mostly” gluten free and am interested to see if I get improved results by commiting to more dietary changes and adding supplmentation with l-tyrosine & l-carnitine.
Re this statement:What does it mean for narcolepsy? Why would narcoleptics have low histamine and a compensatory increase in the number of histmaine-containing neurons?
Q #1: Wouldn’t the incease in histmine-containing neurons have the effect of attacking and destroying hypocretin cells with the net result of causing Narcolepsy in the same way as increased levels of histamine?
Q #2: If a person with Narcolepsy is having an allergic reaction to an external element (ie dust mites) would that not activate histamines, or histmine-containing neurons, to attack hypocretin cells with the net result of causing Narcolepsy?