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WAKIX Increases Histamine Levels in the Brain

The mechanism of action (MOA) of WAKIX in EDS 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 signaling to brain regions important for 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 »
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  1. Nieto-Alamilla G, Marquez-Gomez R, Garcia-Galvez AM, Morales-Figueroa GE, Arias-Montano JA. 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 JC. 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 University Press; 2000:77-98.
  5. Lin JS, 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.