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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 GABAA 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 GABAB 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]
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