Wakefulness-promoting agent

Types

A variety of different classes of drugs have shown wakefulness-promoting effects, including:

• Dopamine reuptake inhibitors like modafinil, armodafinil, mesocarb, phenylpiracetam, and vanoxerine
• Norepinephrine–dopamine reuptake inhibitors like methylphenidate, solriamfetol, mazindol, bupropion, nomifensine, and amineptine
• Norepinephrine–dopamine releasing agents like amphetamine and methamphetamine
• Norepinephrine reuptake inhibitors like atomoxetine, reboxetine, and desipramine
• Norepinephrine releasing agents like ephedrine and selegiline (via its metabolites)
• Dopamine D1 receptor positive allosteric modulators like mevidalen
• Adenosine receptor antagonists like caffeine, paraxanthine, and istradefylline
• Histamine H3 receptor antagonists and inverse agonists like pitolisant and samelisant
• Orexin receptor agonists like danavorexton and suntinorexton
• Nicotinic acetylcholine receptor agonists like nicotine

Other drugs

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

Serotonergic psychedelics, acting as serotonin 5-HT2A receptor agonists, such as LSD, psilocybin, mescaline, and DOM, have wakefulness-promoting effects in animals in addition to their hallucinogenic effects. Relatedly, some psychedelics are associated with mild stimulant-like effects in humans and psychedelics have often been associated with insomnia or sleep disturbances. Similarly to serotonergic psychedelics, the iboga alkaloids and oneirogens ibogaine and noribogaine have been found to promote wakefulness in rodents. Relatedly, low doses of Tabernanthe spp. extracts containing ibogaine have been used pharmaceutically as stimulants in the past.

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.

The GHB and GABAB receptor agonist sodium oxybate or γ-hydroxybutyrate (GHB) has been used in the treatment of narcolepsy. Relatedly, some researchers have classified this drug as a stimulant-like agent. However, GHB is taken at night and only results in improved wakefulness the next day following sleep.

Terminology

The related term "eugeroic" (or "eugregoric") means "vigilance-promoting". 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. However, the term has usually been used to refer specifically to modafinil and its analogues, even to the exclusion of other wakefulness-promoting agents. Moreover, the term has not been widely adopted in the scientific literature. 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".

References

References

1. (September 2004). "What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications". Sleep.
2. (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.
3. (2013). "Stimulants, Wakefulness-promoting Agents, and Nonstimulant Attention Deficit Hyperactivity Disorder Medications". Journal of Experimental & Clinical Medicine.
4. (August 2024). "From past to future: 50 years of pharmacological interventions to treat narcolepsy". Pharmacol Biochem Behav.
5. (February 2017). "Coffee, caffeine, and sleep: A systematic review of epidemiological studies and randomized controlled trials". Sleep Med Rev.
6. (May 2021). "Stimulant Usage by Medical Students for Cognitive Enhancement: A Systematic Review". Cureus.
7. (2016). "Narcolepsy". Springer International Publishing.
8. (April 2020). "Update on the pharmacologic management of narcolepsy: mechanisms of action and clinical implications". Sleep Med.
9. (14 July 2017). "Drug Repositioning". CRC Press.
10. (2015). "Stereochemistry of phenylpiracetam and its methyl derivative: improvement of the pharmacological profile". Chemistry of Heterocyclic Compounds.
11. (February 2007). "Effects of psychiatric medications on sleep and sleep disorders". CNS Neurol Disord Drug Targets.
12. (2021). "The Signaling and Pharmacology of the Dopamine D1 Receptor". Frontiers in Cellular Neuroscience.
13. (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.
14. (November 2020). "Can adenosine A2A receptor antagonists be used to treat cognitive impairment, depression or excessive sleepiness in Parkinson's disease?". Parkinsonism Relat Disord.
15. (2019). "Adenosine and Sleep". Handb Exp Pharmacol.
16. (November 2023). "Effects of Nicotine on the Central Nervous System and Sleep Quality in Relation to Other Stimulants: A Narrative Review". Cureus.
17. (February 2011). "Histamine in the regulation of wakefulness". Sleep Med Rev.
18. (2021). "The Human Hypothalamus - Middle and Posterior Region". Handb Clin Neurol.
19. (2011). "5-HT2C Receptors in the Pathophysiology of CNS Disease". Humana Press.
20. (2020). "The Effects of Daytime Psilocybin Administration on Sleep: Implications for Antidepressant Action". Front Pharmacol.
21. (March 2010). "Serotonin 5-HT(2A) receptor antagonists in the treatment of insomnia: present status and future prospects". Drugs Today (Barc).
22. (23 February 2022). "Psilocin acutely alters sleep-wake architecture and cortical brain activity in laboratory mice". Translational Psychiatry.
23. Kuypers, Kim P. C.. (2024). "Modern CNS Drug Discovery". Springer Nature Switzerland.
24. (1 October 2023). "Learning about STP: A Forgotten Psychedelic from the Summer of Love". History of Pharmacy and Pharmaceuticals.
25. (1991). "[[PiHKAL: A Chemical Love Story]]". Transform Press.
26. (27 April 2018). "Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile". Frontiers in Pharmacology.
27. (2024). "Noribogaine acute administration in rats promotes wakefulness and suppresses REM sleep". Psychopharmacology.
28. (March 2008). "Ibogaine, an anti-addictive drug: pharmacology and time to go further in development. A narrative review". Hum Exp Toxicol.
29. (April 2023). "IUPHAR - invited review - Ibogaine - A legacy within the current renaissance of psychedelic therapy". Pharmacol Res.
30. (3 October 2018). "Advances in pharmaceutical treatment options for narcolepsy". Expert Opinion on Orphan Drugs.
31. (September 2022). "Pharmacologic Management of Excessive Daytime Sleepiness". Sleep Med Clin.
32. (February 2020). "The role of eugeroics in the treatment of affective disorders". Psychiatr Pol.
33. (1995). "Some measures to reduce effects of prolonged sleep deprivation". Neurophysiol Clin.