WAKIX Increases Histamine Levels in the Brain

The mechanism of action (MOA) of WAKIX in EDS in patients 6 years and older with narcolepsy or cataplexy in adult patients with narcolepsy is unclear; however, its efficacy could be mediated through its activity as an antagonist/inverse agonist at H3 receptors.


A different mechanism of action

WAKIX Blocks Histamine From Binding to Presynaptic H3 Autoreceptors1-3

WAKIX Binding to H3 Receptors Increases Histamine Synthesis and Release1,3,4

Histamine Binds to H1 Receptors, Which Increases Communication to Neurons in Brain Regions Important for Sleep and Wakefulness5,6

EDS, excessive daytime sleepiness; H1, histamine 1; H3, histamine 3.

H1 receptors increase neuronal activity, which allows for communication with important brain regions for sleep and wakefulness.1,7,8

H3 receptors help regulate histamine synthesis and release.1 Normally, when synaptic histamine levels are high, histamine binds to H3 autoreceptors to inhibit further synthesis and release of histamine in the brain.1,7

View EDS and cataplexy clinical data in adult patients»Learn more about histamine »


  1. Nieto-Alamilla G, Márquez-Gómez R, García-Gálvez AM, Morales-Figueroa G-E, Arias-Montaño J-A. The histamine H3 receptor: structure, pharmacology, and function. Mol Pharmacol. 2016;90(5):649-673.
  2. Ligneau X, Perrin D, Landais L, et al. BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: preclinical pharmacology. J Pharmacol Exp Ther. 2007;320(1):365-375.
  3. Schwartz J-C. The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol. 2011;163(4):713-721.
  4. Stahl SM. Special properties of receptors. In: Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 2nd ed. Cambridge, UK: Cambridge University Press; 2000:77-98.
  5. Lin J-S, Sergeeva OA, Haas HL. Histamine H3 receptors and sleep-wake regulation. J Pharmacol Exp Ther. 2011;336(1):17-23.
  6. Benarroch EE. Histamine in the CNS: multiple functions and potential neurologic implications. Neurology. 2010;75(16):1472-1479.
  7. Scammell TE, Jackson AC, Franks NP, Wisden W, Dauvilliers Y. Histamine: neural circuits and new medications. Sleep. 2019;42(1). doi:10.1093/sleep/zsy183
  8. Scammell TE, Arrigoni E, Lipton JO. Neural circuitry of wakefulness and sleep. Neuron. 2017;93(4):747-765.