Wakefulness-promoting agent

A wakefulness-promoting agent (WPA), or wake-promoting agent, is a drug that increases wakefulness and arousal.^[1][2][3] They are similar to but distinct from psychostimulants, which not only promote wakefulness but also produce other more overt central nervous system effects, such as improved mood, energy, and motivation.^[1][4] Wakefulness-promoting agents are used to treat narcolepsy and hypersomnia as well as to promote wakefulness and increase performance in healthy people.^[5][6][7]

Wakefulness-promoting agent
Drug class
The chemical structure of modafinil, a widely used wakefulness-promoting agent
Class identifiers
Synonyms	Wakefulness-promoting agent; Wakefulness-promoting drug; Wakefulness promoting medication; Wake-promoting agent; Wake-promoting drug; Wake-promoting medication; WPA
Use	To increase wakefulness and arousal, to reduce sleepiness and sedation
Legal status
In Wikidata

A variety of different classes of drugs have shown wakefulness-promoting effects, including:^[8][5][3][9]

• Dopamine reuptake inhibitors like modafinil, armodafinil, mesocarb, phenylpiracetam, and vanoxerine^{[8][5][9][10][11]}
• Norepinephrine–dopamine reuptake inhibitors like methylphenidate, solriamfetol, mazindol, bupropion, nomifensine, and amineptine^[8][9]
• Norepinephrine–dopamine releasing agents like amphetamine and methamphetamine^[8][9]
• Norepinephrine reuptake inhibitors like atomoxetine and reboxetine^[8][9]
• Norepinephrine releasing agents like ephedrine and selegiline (via its metabolites)^[8][5]
• Dopamine D₁ receptor positive allosteric modulators like mevidalen^[12][13]
• Adenosine receptor antagonists like caffeine, paraxanthine, and istradefylline^{[8][5][14][15]}
• Histamine H₃ receptor antagonists and inverse agonists like pitolisant and samelisant^[9]
• Orexin receptor agonists like danavorexton and suntinorexton^[5]
• Nicotinic acetylcholine receptor agonists like nicotine^[1][16]

Histamine and other histamine H₁ receptor agonists also have wakefulness-promoting effects.^[9][17][18] However, H₁ receptor agonists as drugs are limited by their mediation of allergy-type symptoms.^[18]

Certain other drugs are being studied as wakefulness-promoting agents as well, including GABA_A receptor antagonists and negative allosteric modulators like clarithromycin, flumazenil, and pentylenetetrazol (pentetrazol), among others.^[19]

Aside from the above-described wakefulness-promoting agents, the GHB and GABA_B receptor agonist sodium oxybate or γ-hydroxybutyrate (GHB) has been used in the treatment of narcolepsy.^{[20][8][5][3]} Relatedly, some researchers have classified this drug as a stimulant-like agent.^[20] However, GHB is taken at night and only results in improved wakefulness the next day following sleep.^[20]

The related term "eugeroic" (or "eugregoric") means "vigilance-promoting".^[5] It was introduced in 1987 in the French literature and has been used as an alternative term to refer to wakefulness-promoting drugs and to distinguish them from psychostimulants.^[5] However, the term has usually been used to refer specifically to modafinil and its analogues, even to the exclusion of other wakefulness-promoting agents.^[5][21][22] Moreover, the term has not been widely adopted in the scientific literature.^[5] The discovery of wakefulness-promoting neurons and the orexin neuropeptides has prompted a terminological shift away from the concept of "vigilance-promoting" to "wakefulness-promoting".^[5]

References

1. Boutrel B, Koob GF (September 2004). "What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications". Sleep. 27 (6): 1181–1194. doi:10.1093/sleep/27.6.1181. PMID 15532213.
2. Dell'Osso B, Dobrea C, Cremaschi L, Arici C, Altamura AC (December 2014). "Wake-promoting pharmacotherapy for psychiatric disorders". Curr Psychiatry Rep. 16 (12): 524. doi:10.1007/s11920-014-0524-2. PMID 25312027.
3. Zhan S, Ye H, Li N, Zhang Y, Cheng Y, Wang Y, Hu S, Hou Y (2023). "Comparative Efficacy and Safety of Multiple Wake-Promoting Agents for the Treatment of Excessive Daytime Sleepiness in Narcolepsy: A Network Meta-Analysis". Nat Sci Sleep. 15: 217–230. doi:10.2147/NSS.S404113. PMC 10112483. PMID 37082610.
4. Chang, Shen-Chieh; Shen, Winston W. (2013). "Stimulants, Wakefulness-promoting Agents, and Nonstimulant Attention Deficit Hyperactivity Disorder Medications". Journal of Experimental & Clinical Medicine. 5 (6): 210–216. doi:10.1016/j.jecm.2013.10.010.
5. Konofal E (August 2024). "From past to future: 50 years of pharmacological interventions to treat narcolepsy". Pharmacol Biochem Behav. 241: 173804. doi:10.1016/j.pbb.2024.173804. PMID 38852786.
6. Clark I, Landolt HP (February 2017). "Coffee, caffeine, and sleep: A systematic review of epidemiological studies and randomized controlled trials". Sleep Med Rev. 31: 70–78. doi:10.1016/j.smrv.2016.01.006. PMID 26899133.
7. Plumber N, Majeed M, Ziff S, Thomas SE, Bolla SR, Gorantla VR (May 2021). "Stimulant Usage by Medical Students for Cognitive Enhancement: A Systematic Review". Cureus. 13 (5): e15163. doi:10.7759/cureus.15163. PMC 8216643. PMID 34178492.
8. Nishino, Seiji; Kotorii, Nozomu (2016). "Modes of Action of Drugs Related to Narcolepsy: Pharmacology of Wake-Promoting Compounds and Anticataplectics". Narcolepsy. Cham: Springer International Publishing. pp. 307–329. doi:10.1007/978-3-319-23739-8_22. ISBN 978-3-319-23738-1.
9. Thorpy MJ, Bogan RK (April 2020). "Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications". Sleep Med. 68: 97–109. doi:10.1016/j.sleep.2019.09.001. PMID 32032921.
10. Macolino-Kane, Christine M.; Ciallella, John R.; Lipinski, Christopher A.; Reaume, Andrew G. (14 July 2017). "Phenotypic Screening". Drug Repositioning (PDF). Frontiers in Neurotherapeutics. Boca Raton: CRC Press, [2017]: CRC Press. p. 121–145. doi:10.4324/9781315373669-7. ISBN 978-1-315-37366-9.{{cite book}}: CS1 maint: location (link)
11. Veinberg G, Vavers E, Orlova N, Kuznecovs J, Domracheva I, Vorona M, Zvejniece L, Dambrova M (2015). "Stereochemistry of phenylpiracetam and its methyl derivative: improvement of the pharmacological profile". Chemistry of Heterocyclic Compounds. 51 (7): 601–606. doi:10.1007/s10593-015-1747-9. ISSN 0009-3122. Phenylpiracetam was originally designed as a nootropic drug for the sustenance and improvement of the physical condition and cognition abilities of Soviet space crews.2 Later, especially during the last decade, phenylpiracetam was introduced into general clinical practice in Russia and in some Eastern European countries. The possible target receptors and mechanisms for the acute activity of this drug remained unclear, until very recently it was found that (R)-phenylpiracetam (5) (MRZ-9547) is a selective dopamine transporter inhibitor that moderately stimulates striatal dopamine release.19
12. Jones-Tabah J, Mohammad H, Paulus EG, Clarke PB, Hébert TE (2021). "The Signaling and Pharmacology of the Dopamine D1 Receptor". Frontiers in Cellular Neuroscience. 15: 806618. doi:10.3389/fncel.2021.806618. PMC 8801442. PMID 35110997.
13. McCarthy AP, Svensson KA, Shanks E, Brittain C, Eastwood BJ, Kielbasa W, et al. (March 2022). "The Dopamine D1 Receptor Positive Allosteric Modulator Mevidalen (LY3154207) Enhances Wakefulness in the Humanized D1 Mouse and in Sleep-Deprived Healthy Male Volunteers". The Journal of Pharmacology and Experimental Therapeutics. 380 (3): 143–152. doi:10.1124/jpet.121.000719. PMID 34893551. S2CID 247363215.
14. Jenner P, Mori A, Kanda T (November 2020). "Can adenosine A2A receptor antagonists be used to treat cognitive impairment, depression or excessive sleepiness in Parkinson's disease?". Parkinsonism Relat Disord. 80 Suppl 1: S28–S36. doi:10.1016/j.parkreldis.2020.09.022. PMID 33349577.
15. Lazarus M, Chen JF, Huang ZL, Urade Y, Fredholm BB (2019). "Adenosine and Sleep". Handb Exp Pharmacol. Handbook of Experimental Pharmacology. 253: 359–381. doi:10.1007/164_2017_36. ISBN 978-3-030-11270-7. PMID 28646346.
16. Singh N, Wanjari A, Sinha AH (November 2023). "Effects of Nicotine on the Central Nervous System and Sleep Quality in Relation to Other Stimulants: A Narrative Review". Cureus. 15 (11): e49162. doi:10.7759/cureus.49162. PMC 10733894. PMID 38130519.
17. Thakkar MM (February 2011). "Histamine in the regulation of wakefulness". Sleep Med Rev. 15 (1): 65–74. doi:10.1016/j.smrv.2010.06.004. PMC 3016451. PMID 20851648.
18. Panula P (2021). "Histamine receptors, agonists, and antagonists in health and disease". The Human Hypothalamus - Middle and Posterior Region. Handbook of Clinical Neurology. Vol. 180. pp. 377–387. doi:10.1016/B978-0-12-820107-7.00023-9. ISBN 978-0-12-820107-7. PMID 34225942. {{cite book}}: |journal= ignored (help)
19. Takahashi, Tatsunori; Noriaki, Sakai; Matsumura, Mari; Li, Chenyu; Takahashi, Kayo; Nishino, Seiji (3 October 2018). "Advances in pharmaceutical treatment options for narcolepsy". Expert Opinion on Orphan Drugs. 6 (10): 597–610. doi:10.1080/21678707.2018.1521267. ISSN 2167-8707.
20. Ono T, Takenoshita S, Nishino S (September 2022). "Pharmacologic Management of Excessive Daytime Sleepiness". Sleep Med Clin. 17 (3): 485–503. doi:10.1016/j.jsmc.2022.06.012. PMID 36150809.
21. Urban AE, Cubała WJ (February 2020). "The role of eugeroics in the treatment of affective disorders". Psychiatr Pol. 54 (1): 21–33. doi:10.12740/PP/OnlineFirst/90687. PMID 32447354.
22. Lagarde D, Batejat D (1995). "Some measures to reduce effects of prolonged sleep deprivation". Neurophysiol Clin. 25 (6): 376–385. doi:10.1016/0987-7053(96)84911-2. PMID 8904200.