View source for Hypnotic

{{Short description|Drug whose use induces sleep}}
{{About|the class of prescription medicines|the state of mind|Hypnosis|other uses}}
{{Redirect|Sleeping pills|the 2003 film|Sleeping Pills (film)}}
{{Infobox drug class 
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| Image               = File:Stilnoct2.JPG
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| Caption             = [[Zolpidem]] tablets, a common but potent hypnotic used for insomnia.
| Width               = 200px
| Pronounce           = 
| Synonyms            = Sedative; Somnifacient; Soporific; Sleeping pill; Sleep aid; Sedative–hypnotic; Hypnotica
<!-- Class identifiers -->
| Use                 = [[Insomnia]], [[hypersomnia]], [[narcolepsy]]
| ATC_prefix          = 
| Mode_of_action      = 
| Mechanism_of_action = Various
| Biological_target   = Various
| Chemical_class      = Various
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| Drugs.com           = <!-- {{Drugs.com|drug-class|?}} -->
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| MeshID              = 
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| legal_status        = Variable
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A '''hypnotic''' (from [[Ancient Greek|Greek]] ''Hypnos'', sleep<ref>{{Cite web|title=Definition of HYPNOTIC|url=https://www.merriam-webster.com/dictionary/hypnotic|access-date=2021-09-27|website=www.merriam-webster.com|language=en}}</ref>), also known as a '''somnifacient''' or '''soporific''', and commonly known as '''sleeping pills''', are a class of [[psychoactive drug]]s whose primary function is to [[sleep induction|induce sleep]]<ref name="urlDorlands Medical Dictionary:hypnotic">{{cite web |url= http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jsp?pg=/ppdocs/us/common/dorlands/dorland/four/000051451.htm |title=Dorlands Medical Dictionary:hypnotic |website=Mercksource.com |archive-url=https://web.archive.org/web/20081211091401/http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jsp?pg=%2Fppdocs%2Fus%2Fcommon%2Fdorlands%2Fdorland%2Ffour%2F000051451.htm |archive-date=2008-12-11 }}</ref> and to treat [[insomnia]] (sleeplessness). Some hypnotics are also used to treat [[narcolepsy]] and [[hypersomnia]] by improving sleep at night and thereby reducing [[daytime sleepiness]].<ref name="Mayer2012" /><ref name="Broughton2015" /> Certain hypnotics can be used to treat [[non-restorative sleep]] and associated symptoms in conditions like [[fibromyalgia]] as well.<ref name="Staud2011" /><ref name="Broughton2015" /><ref name="Moldofsky2008">{{cite journal | vauthors = Moldofsky H | title = The significance, assessment, and management of nonrestorative sleep in fibromyalgia syndrome | journal = CNS Spectr | volume = 13 | issue = 3 Suppl 5 | pages = 22–26 | date = March 2008 | pmid = 18323770 | doi = 10.1017/s1092852900026808 | url = }}</ref><ref name="Moldofsky2015">{{cite book | last=Moldofsky | first=Harvey | title=Sleep Medicine | chapter=Nonrestorative Sleep, Musculoskeletal Pain, Fatigue in Rheumatic Disorders, and Allied Syndromes: A Historical Perspective | publisher=Springer New York | publication-place=New York, NY | date=2015 | isbn=978-1-4939-2088-4 | pmc=7122008 | doi=10.1007/978-1-4939-2089-1_48 | doi-access=free | pages=423–431}}</ref>

This group of drugs is related to [[sedative]]s''. ''Whereas the term sedative describes drugs that serve to calm or [[Anxiolytic|relieve anxiety]], the term hypnotic generally describes drugs whose main purpose is to initiate, sustain, or lengthen sleep. Because these two functions frequently overlap, and because drugs in this class generally produce dose-dependent effects (ranging from [[anxiolysis]] to [[loss of consciousness]]), they are often referred to collectively as '''sedative–hypnotic''' drugs.<ref name="Pharmacologic Basis of Therapeutics">{{cite book| vauthors = Brunton LL, Parker K, Lazo KL, Buxton I, Blumenthal D |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |publisher=The McGraw-Hill Companies, Inc. |year=2006 |edition=11th |chapter-url=http://accessmedicine.mhmedical.com/content.aspx?bookid=374&sectionid=41266223 |chapter=17: Hypnotics and Sedatives |isbn=978-0-07-146804-6 |access-date=2014-02-06}}</ref>

Hypnotic drugs are regularly prescribed for insomnia and other sleep disorders, with over 95% of insomnia patients being prescribed hypnotics in some countries.<ref name="npsnews">{{cite web |url=http://www.nps.org.au/health_professionals/publications/nps_news/current/nps_news_67 |title=NPS News 67: Addressing hypnotic medicines use in primary care |author=National Prescribing Service |date=2 February 2010 |access-date=19 March 2010 |archive-url=https://web.archive.org/web/20110222130542/http://www.nps.org.au/health_professionals/publications/nps_news/current/nps_news_67 |archive-date=22 February 2011 }}</ref> Many hypnotic drugs are habit-forming and—due to many factors known to disturb the human sleep pattern—a physician may instead recommend changes in the environment before and during sleep, better [[sleep hygiene]], the avoidance of caffeine and [[alcohol (drug)|alcohol]] or other stimulating substances, or behavioral interventions such as [[cognitive behavioral therapy for insomnia]] (CBT-I), before prescribing medication for sleep. When prescribed, hypnotic medication should be used for the shortest period of time necessary.<ref>{{cite journal | vauthors = Mendels J | title = Criteria for selection of appropriate benzodiazepine hypnotic therapy | journal = The Journal of Clinical Psychiatry | volume = 52 | issue = Suppl | pages = 42–46 | date = September 1991 | pmid = 1680126 | series = 52 }}</ref>

Among individuals with sleep disorders, 13.7% are taking or prescribed [[nonbenzodiazepine]]s (Z-drugs), while 10.8% are taking [[benzodiazepine]]s, as of 2010, in the USA.<ref>{{cite journal | vauthors = Kaufmann CN, Spira AP, Alexander GC, Rutkow L, Mojtabai R | title = Trends in prescribing of sedative-hypnotic medications in the USA: 1993-2010 | journal = Pharmacoepidemiology and Drug Safety | volume = 25 | issue = 6 | pages = 637–645 | date = June 2016 | pmid = 26711081 | pmc = 4889508 | doi = 10.1002/pds.3951 }}</ref> Early classes of drugs, such as [[barbiturate]]s, have fallen out of use in most practices but are still prescribed for some patients. In children, prescribing hypnotics is not currently acceptable—unless used to treat [[night terror]]s or [[sleepwalking]].<ref>{{cite book| vauthors = Gelder M, Mayou R, Geddes J |year=2005 |title=Psychiatry |edition=3rd |place=New York |publisher=Oxford |page=238}}</ref> Elderly people are more sensitive to potential side effects of daytime fatigue and [[cognitive impairment]], and a [[meta-analysis]] found that the risks generally outweigh any marginal benefits of hypnotics in the elderly.<ref>{{cite journal | vauthors = Glass J, Lanctôt KL, Herrmann N, Sproule BA, Busto UE | title = Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits | journal = BMJ | volume = 331 | issue = 7526 | page = 1169 | date = November 2005 | pmid = 16284208 | pmc = 1285093 | doi = 10.1136/bmj.38623.768588.47 }}</ref> A review of the literature regarding benzodiazepine hypnotics and Z-drugs concluded that these drugs have adverse effects, such as [[substance dependence|dependence]] and accidents, and that optimal treatment uses the lowest effective dose for the shortest therapeutic time, with gradual discontinuation to improve health without worsening of sleep.<ref>{{cite journal | vauthors = <!--none listed--> | title = What's wrong with prescribing hypnotics? | journal = Drug and Therapeutics Bulletin | volume = 42 | issue = 12 | pages = 89–93 | date = December 2004 | pmid = 15587763 | doi = 10.1136/dtb.2004.421289 | s2cid = 40188442 }}</ref>

Falling outside the above-mentioned categories, the neurohormone [[melatonin (medication)|melatonin]] and its analogues (e.g., [[ramelteon]]) serve a hypnotic function.<ref>{{cite journal | vauthors = Zhdanova IV | title = Melatonin as a hypnotic: pro | journal = Sleep Medicine Reviews | volume = 9 | issue = 1 | pages = 51–65 | date = February 2005 | pmid = 15649738 | doi = 10.1016/j.smrv.2004.04.003 }}</ref>

==Types==
===GABA<sub>A</sub> receptor positive allosteric modulators===
{{Main|GABAA receptor positive allosteric modulator}}

====Benzodiazepines====
{{Main|Benzodiazepine#Insomnia}}

[[Benzodiazepine]]s can be useful for short-term treatment of insomnia. Their use beyond 2 to 4 weeks is not recommended due to the risk of dependence. It is preferred that benzodiazepines be taken intermittently and at the lowest effective dose. They improve sleep-related problems by shortening the time spent in bed before falling asleep, prolonging sleep time, and reducing wakefulness.<ref name="nice-hypnotics">{{cite web|title=Technology Appraisal Guidance 77. Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia |url=http://www.nice.org.uk/nicemedia/pdf/TA077fullguidance.pdf |publisher=National Institute for Clinical Excellence |date=April 2004 |access-date=2009-07-26 |archive-url=https://web.archive.org/web/20081203063917/http://www.nice.org.uk/nicemedia/pdf/TA077fullguidance.pdf |archive-date=2008-12-03 }}</ref><ref name="pmid17853625">{{cite journal | vauthors = Ramakrishnan K, Scheid DC | title = Treatment options for insomnia | journal = American Family Physician | volume = 76 | issue = 4 | pages = 517–526 | date = August 2007 | pmid = 17853625 | url = http://www.aafp.org/afp/2007/0815/p517.html }}</ref> Like [[Alcohol (drug)|alcohol]], benzodiazepines are commonly used to treat insomnia in the short-term (both prescribed and self-medicated), but worsen sleep in the long-term. While benzodiazepines can put people to sleep (i.e., inhibit NREM stage 1 and 2 sleep), while asleep, the drugs disrupt [[sleep architecture]] by decreasing sleep time, delaying time to REM sleep, and decreasing deep [[slow-wave sleep]] (the most restorative part of sleep for both energy and mood).<ref>{{cite journal | vauthors = Ashton H | title = The diagnosis and management of benzodiazepine dependence | journal = Current Opinion in Psychiatry | volume = 18 | issue = 3 | pages = 249–255 | date = May 2005 | pmid = 16639148 | doi = 10.1097/01.yco.0000165594.60434.84 | s2cid = 1709063 }}</ref><ref>{{cite journal | vauthors = Morin CM, Bélanger L, Bastien C, Vallières A | title = Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse | journal = Behaviour Research and Therapy | volume = 43 | issue = 1 | pages = 1–14 | date = January 2005 | pmid = 15531349 | doi = 10.1016/j.brat.2003.12.002 }}</ref><ref>{{cite journal | vauthors = Poyares D, Guilleminault C, Ohayon MM, Tufik S | title = Chronic benzodiazepine usage and withdrawal in insomnia patients | journal = Journal of Psychiatric Research | volume = 38 | issue = 3 | pages = 327–334 | date = 2004-06-01 | pmid = 15003439 | doi = 10.1016/j.jpsychires.2003.10.003 }}</ref>

Other drawbacks of hypnotics, including benzodiazepines, are possible [[Drug tolerance|tolerance]] to their effects, [[rebound insomnia]], and reduced slow-wave sleep and a withdrawal period typified by rebound insomnia and a prolonged period of anxiety and agitation.<ref name="handbook_of_integrative">{{Cite book| vauthors = Maiuro RD |title=Handbook of Integrative Clinical Psychology, Psychiatry, and Behavioral Medicine: Perspectives, Practices, and Research |date=13 December 2009 |publisher=Springer Publishing Company |url=https://books.google.com/books?id=4Tkdm1vRFbUC |isbn=978-0-8261-1094-7 |pages=128–30}}</ref><ref name="ahrq" /> The list of benzodiazepines approved for the treatment of insomnia is similar among most countries, but which benzodiazepines are officially designated as first-line hypnotics prescribed for the treatment of insomnia can vary distinctly between countries.<ref name="pmid17853625" /> Longer-acting benzodiazepines, such as [[nitrazepam]] and [[diazepam]], have residual effects that may persist into the next day and are, in general, not recommended.<ref name="nice-hypnotics" />

It is not clear whether the newer [[nonbenzodiazepine]] (Z-drug) hypnotics are better than the short-acting benzodiazepines. The efficacy of these two groups of medications is similar.<ref name="nice-hypnotics" /><ref name="ahrq" /> According to the US [[Agency for Healthcare Research and Quality]], indirect comparison indicates that side effects from benzodiazepines may be about twice as frequent as from nonbenzodiazepines.<ref name="ahrq">{{cite journal | vauthors = Buscemi N, Vandermeer B, Friesen C, Bialy L, Tubman M, Ospina M, Klassen TP, Witmans M | display-authors = 6 | title = Manifestations and management of chronic insomnia in adults | journal = Evidence Report/Technology Assessment | issue = 125 | pages = 1–10 | date = June 2005 | pmid = 15989374 | doi = 10.1037/e439752005-001 | publisher = Agency for Healthcare Research and Quality | pmc = 4781279 }}</ref> Some experts suggest using nonbenzodiazepines preferentially as a first-line long-term treatment of insomnia.<ref name="pmid17853625" /> However, the UK [[National Institute for Health and Clinical Excellence]] (NICE) did not find any convincing evidence in favor of Z-drugs. A NICE review pointed out that short-acting Z-drugs were inappropriately compared in clinical trials with long-acting benzodiazepines. There have been no trials comparing short-acting Z-drugs with appropriate doses of short-acting benzodiazepines. Based on this, NICE recommended choosing the hypnotic based on cost and the patient's preference.<ref name="nice-hypnotics" />

Older adults should not use benzodiazepines to treat insomnia unless other treatments have failed to be effective.<ref name="AGSfive">{{cite web|author1=American Geriatrics Society |author1-link = American Geriatrics Society |title=Five Things Physicians and Patients Should Question |publisher=American Geriatrics Society |work=[[Choosing Wisely]]: an initiative of the [[ABIM Foundation]] |url=http://www.choosingwisely.org/doctor-patient-lists/american-geriatrics-society/ |access-date=August 1, 2013}}, which cites
*{{cite journal | vauthors = Finkle WD, Der JS, Greenland S, Adams JL, Ridgeway G, Blaschke T, Wang Z, Dell RM, VanRiper KB | display-authors = 6 | title = Risk of fractures requiring hospitalization after an initial prescription for zolpidem, alprazolam, lorazepam, or diazepam in older adults | journal = Journal of the American Geriatrics Society | volume = 59 | issue = 10 | pages = 1883–1890 | date = October 2011 | pmid = 22091502 | doi = 10.1111/j.1532-5415.2011.03591.x | s2cid = 23523742 }}
*{{cite journal | vauthors = Allain H, Bentué-Ferrer D, Polard E, Akwa Y, Patat A | title = Postural instability and consequent falls and hip fractures associated with use of hypnotics in the elderly: a comparative review | journal = Drugs & Aging | volume = 22 | issue = 9 | pages = 749–765 | year = 2005 | pmid = 16156679 | doi = 10.2165/00002512-200522090-00004 | s2cid = 9296501 }}
*{{cite journal | title = American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults | journal = Journal of the American Geriatrics Society | volume = 60 | issue = 4 | pages = 616–631 | date = April 2012 | pmid = 22376048 | pmc = 3571677 | doi = 10.1111/j.1532-5415.2012.03923.x | author1 = American Geriatrics Society 2012 Beers Criteria Update Expert Panel }}</ref> When benzodiazepines are used, patients, their caretakers, and their physician should discuss the increased risk of harms, including evidence which shows twice the incidence of [[traffic collisions]] among driving patients, as well as falls and hip fracture for all older patients.<ref name="npsnews" /><ref name="AGSfive" />

Their [[mechanism of action]] is primarily at [[GABAA receptor|GABA<sub>A</sub> receptors]].<ref name="isbn0-12-088397-X">{{cite book| vauthors = Olsen RW, Betz H | veditors = Siegel GJ, Albers RW, Brady S, Price DD |title=Basic Neurochemistry: Molecular, Cellular and Medical Aspects |edition=7th |publisher=Elsevier |year=2006 |pages=291–302 |chapter=GABA and glycine |isbn=978-0-12-088397-4}}</ref>

====Nonbenzodiazepines====
{{Main|Nonbenzodiazepine}}

[[Nonbenzodiazepine]]s (Z-drugs) are a class of [[psychoactive drug]]s that are "benzodiazepine-like" in nature. Nonbenzodiazepine [[pharmacodynamics]] are almost entirely the same as benzodiazepine drugs, and therefore entail similar benefits, side effects, and risks. Nonbenzodiazepines, however, have dissimilar or different chemical structures, and are unrelated to benzodiazepines on a molecular level.<ref name="pmid9640488a">{{cite journal |vauthors=Wagner J, Wagner ML, Hening WA |date=June 1998 |title=Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia |journal=The Annals of Pharmacotherapy |volume=32 |issue=6 |pages=680–691 |doi=10.1345/aph.17111 |pmid=9640488 |s2cid=34250754}}</ref><ref>{{cite journal | vauthors = Siriwardena AN, Qureshi Z, Gibson S, Collier S, Latham M | title = GPs' attitudes to benzodiazepine and 'Z-drug' prescribing: a barrier to implementation of evidence and guidance on hypnotics | journal = The British Journal of General Practice | volume = 56 | issue = 533 | pages = 964–967 | date = December 2006 | pmid = 17132386 | pmc = 1934058 }}</ref>

Examples include [[zopiclone]] (Imovane), [[eszopiclone]] (Lunesta), [[zaleplon]] (Sonata), and [[zolpidem]] (Ambien). Since the generic names of all drugs of this type start with ''Z'', they are often referred to as ''Z-drugs''.<ref>{{cite journal | last1=Ryba | first1=Nicole | last2=Rainess | first2=Rebecca | title=Z-drugs and Falls: A Focused Review of the Literature | journal=The Senior Care Pharmacist | date=2020 | volume=35 | issue=12 | pages=549–554 | doi=10.4140/tcp.n.2020.549 | pmid=33258763 }}</ref>

Research on nonbenzodiazepines is new and conflicting. A review by a team of researchers suggests the use of these drugs for people who have trouble falling asleep (but not staying asleep),<ref group="note">Because the drugs have a shorter [[elimination half life]] they are metabolized more quickly: nonbenzodiazepines zaleplon and zolpidem have a half-life of 1 and 2 hours (respectively); for comparison, the benzodiazepine clonazepam has a half-life of about 30 hours. This makes the drug suitable for sleep-onset difficulty, but the team noted sustained sleep efficacy was unclear.</ref> as next-day impairments were minimal.<ref name="pmid15746509">{{cite journal | vauthors = Benca RM | title = Diagnosis and treatment of chronic insomnia: a review | journal = Psychiatric Services | volume = 56 | issue = 3 | pages = 332–343 | date = March 2005 | pmid = 15746509 | doi = 10.1176/appi.ps.56.3.332 | quote = Evidence for the utility of currently available nonbenzodiazepine hypnotics points to their primary efficacy as sleep-onset, rather than as sleep-maintenance, agents. Once again, longer-term randomized, double-blind, controlled studies that demonstrate the efficacy of these agents have not been performed, but safety over the longer term has been demonstrated in open-label studies, with minimal evidence of rebound phenomena. By comparison with benzodiazepines, there has been less evidence of subjective and objective next-day residual effects associated with zolpidem or subjective next-day impairment with zaleplon, even when the latter has been delivered in the middle of the night. }}</ref> The team noted that the safety of these drugs had been established, but called for more research into their long-term effectiveness in treating insomnia. Other evidence suggests that [[drug tolerance|tolerance]] to nonbenzodiazepines may be slower to develop than with benzodiazepines.{{failed verification|date=February 2014}} A different team was more skeptical, finding little benefit over benzodiazepines.<ref name="pmid9640488b">{{cite journal | vauthors = Wagner J, Wagner ML, Hening WA | title = Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia | journal = The Annals of Pharmacotherapy | volume = 32 | issue = 6 | pages = 680–691 | date = June 1998 | pmid = 9640488 | doi = 10.1345/aph.17111 | quote = New developments in benzodiazepine receptor pharmacology have introduced novel nonbenzodiazepine hypnotics that provide comparable efficacy to benzodiazepines. Although they may possess theoretical advantages over benzodiazepines based on their unique pharmacologic profiles, they offer few, if any, significant advantages in terms of adverse effects. | s2cid = 34250754 }}</ref>

====Barbiturates====
{{Main|Barbiturate}}

[[Barbiturate]]s are drugs that act as [[central nervous system]] [[depressant]]s, and can therefore produce a broad spectrum of effects, from mild [[sedation]] to total [[anesthesia]]. They are also effective as [[anxiolytic]]s, hypnotics, and [[anticonvulsant]] effects; however, these effects are somewhat weak, preventing barbiturates from being used in [[surgery]] in the absence of other analgesics. They have dependence liability, both [[physical dependence|physical]] and [[psychological dependence|psychological]]. Barbiturates have now largely been replaced by [[benzodiazepine]]s in routine medical practice&nbsp;– such as in the treatment of anxiety and insomnia&nbsp;– mainly because benzodiazepines are significantly less dangerous in [[drug overdose|overdose]]. However, barbiturates are still used in general anesthesia, for [[epilepsy]], and for [[assisted suicide]]. The principal [[mechanism of action]] of barbiturates is believed to be [[positive allosteric modulator|positive allosteric modulation]] of [[GABAA|GABA<sub>A</sub> receptor]]s.<ref>{{cite journal | vauthors = Löscher W, Rogawski MA | title = How theories evolved concerning the mechanism of action of barbiturates | journal = Epilepsia | volume = 53 | issue = Suppl 8 | pages = 12–25 | date = December 2012 | pmid = 23205959 | doi = 10.1111/epi.12025 | s2cid = 4675696 | doi-access = free }}</ref> Barbiturates are derivatives of [[barbituric acid]]. Examples include [[amobarbital]], [[pentobarbital]], [[phenobarbital]], [[secobarbital]], and [[sodium thiopental]].

====Quinazolinones====
{{Main|Quinazolinone|Methaqualone}}

[[Quinazolinone]]s are also a class of drugs that function as hypnotics/sedatives that contain a 4-quinazolinone core. Examples of quinazolinones include [[cloroqualone]], [[diproqualone]], [[etaqualone]] (Aolan, Athinazone, Ethinazone), [[mebroqualone]], [[afloqualone]] (Arofuto), [[mecloqualone]] (Nubarene, Casfen), and [[methaqualone]] (Quaalude). This class of drugs has been largely discontinued and is no longer used clinically.

====Neurosteroids====
{{Main|Neurosteroid}}

[[Oral administration|Oral]] [[progesterone (medication)|progesterone]] (Prometrium) [[drug metabolism|metabolize]]s into [[neurosteroid]]s including [[allopregnanolone]] and [[pregnanolone]] which act as [[potency (pharmacology)|potent]] GABA<sub>A</sub> receptor positive allosteric modulators.<ref name="GoletianiKeithGorsky2007">{{cite journal | vauthors = Goletiani NV, Keith DR, Gorsky SJ | title = Progesterone: review of safety for clinical studies | journal = Exp Clin Psychopharmacol | volume = 15 | issue = 5 | pages = 427–444 | year = 2007 | pmid = 17924777 | doi = 10.1037/1064-1297.15.5.427 | url = https://www.researchgate.net/publication/5919868}}</ref><ref name="Piette2020">{{cite journal | vauthors = Piette PC | title = The pharmacodynamics and safety of progesterone | journal = Best Pract Res Clin Obstet Gynaecol | volume = 69 | issue = | pages = 13–29 | date = November 2020 | pmid = 32739288 | doi = 10.1016/j.bpobgyn.2020.06.002 | url = }}</ref><ref name="BäckströmDasBixo2022">{{cite journal | vauthors = Bäckström T, Das R, Bixo M | title = Positive GABAA receptor modulating steroids and their antagonists: Implications for clinical treatments | journal = J Neuroendocrinol | volume = 34 | issue = 2 | article-number = e13013 | date = February 2022 | pmid = 34337790 | doi = 10.1111/jne.13013 | url = }}</ref> As a result, oral progesterone can [[dose dependence|dose-dependently]] produce [[side effect]]s including [[dizziness]], [[drowsiness]], [[sedation]], [[somnolence]], [[fatigue]], [[anxiolytic|anxiety reduction]], [[euphoria]], and [[cognitive impairment]].<ref name="Wang-ChengNeuner2007">{{cite book | vauthors = Wang-Cheng R, Neuner JM, Barnabei VM | title = Menopause | url = https://books.google.com/books?id=mPs5Ly71OCQC&pg=PA97 | year = 2007 | publisher = ACP Press | isbn = 978-1-930513-83-9 | page = 97}}</ref><ref name="BergemannRiecher-Rössler2005">{{cite book | vauthors =  Bergemann N, Ariecher-Rössler A | title = Estrogen Effects in Psychiatric Disorders | url = https://books.google.com/books?id=L4YQ50SbBnsC&pg=PA179 | date = 27 December 2005 | publisher = Springer Science & Business Media | isbn = 978-3-211-27063-9 | page = 179}}</ref><ref name="BäckströmBixoJohansson2014">{{cite journal | vauthors = Bäckström T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, Savic I, Strömberg J, Timby E, van Broekhoven F, van Wingen G | title = Allopregnanolone and mood disorders | journal = Prog. Neurobiol. | volume = 113 | pages = 88–94 | year = 2014 | pmid = 23978486 | doi = 10.1016/j.pneurobio.2013.07.005 | s2cid = 207407084 }}</ref> For this reason, oral progesterone is often taken at night before bed.<ref name="Stein2005">{{cite journal | vauthors = Stein DG | title = The case for progesterone | journal = Ann N Y Acad Sci | volume = 1052 | issue = 1| pages = 152–169 | date = June 2005 | pmid = 16024758 | doi = 10.1196/annals.1347.011 | bibcode = 2005NYASA1052..152S | url = }}</ref> Oral progesterone taken before bed has been found to improve multiple sleep outcomes in clinical studies.<ref name="NolanLiangCheung2021">{{cite journal | vauthors = Nolan BJ, Liang B, Cheung AS | title = Efficacy of Micronized Progesterone for Sleep: A Systematic Review and Meta-analysis of Randomized Controlled Trial Data | journal = J Clin Endocrinol Metab | volume = 106 | issue = 4 | pages = 942–951 | date = March 2021 | pmid = 33245776 | doi = 10.1210/clinem/dgaa873 | url = }}</ref><ref name="Mirkin2018">{{cite journal | vauthors = Mirkin S | title = Evidence on the use of progesterone in menopausal hormone therapy | journal = Climacteric | volume = 21 | issue = 4 | pages = 346–354 | date = August 2018 | pmid = 29630427 | doi = 10.1080/13697137.2018.1455657 | url = }}</ref> [[Zuranolone]] is a [[synthetic compound|synthetic]] [[structural analog|analogue]] of allopregnanolone that likewise acts as a GABA<sub>A</sub> receptor positive allosteric modulator but is [[oral administration|orally active]].<ref name="MareckiKałuskaKolanek2023">{{cite journal | vauthors = Marecki R, Kałuska J, Kolanek A, Hakało D, Waszkiewicz N | title = Zuranolone - synthetic neurosteroid in treatment of mental disorders: narrative review | journal = Front Psychiatry | volume = 14 | issue = | article-number = 1298359 | date = 2023 | pmid = 38116383 | pmc = 10729607 | doi = 10.3389/fpsyt.2023.1298359 | doi-access = free | url = }}</ref> It is under development for the treatment of insomnia and is in [[Phases of clinical research#Phase III|phase 3]] [[clinical trial]]s for this indication as of September 2025.<ref name="KimKim2024">{{cite journal | vauthors = Kim WJ, Kim HS | title = Emerging and upcoming therapies in insomnia | journal = Transl Clin Pharmacol | volume = 32 | issue = 1 | pages = 1–17 | date = March 2024 | pmid = 38586124 | pmc = 10990727 | doi = 10.12793/tcp.2024.32.e5 | url = }}</ref><ref name="AdisInsight-Zuranolone">{{cite web | title=Biogen/SAGE Therapeutics | website=AdisInsight | date=22 September 2025 | url=https://adisinsight.springer.com/drugs/800043382 | access-date=2 October 2025}}</ref>

====Others====
{{See also|Sleep induction#Alcohol}}

Other GABA<sub>A</sub> receptor positive allosteric modulators with hypnotic effects include [[alcohol (drug)|alcohol]] (ethanol), [[chloral hydrate]], [[ethyl carbamate|urethane]] (ethyl carbamate), [[isoflurane]], [[allopregnanolone]] (brexanolone), and [[propofol]], among others.<ref name="LuGreco2006">{{cite journal | vauthors = Lu J, Greco MA | title = Sleep circuitry and the hypnotic mechanism of GABAA drugs | journal = J Clin Sleep Med | volume = 2 | issue = 2 | pages = S19–S26 | date = April 2006 | pmid = 17557503 | doi = 10.5664/jcsm.26527| url = }}</ref><ref name="Pleuvry2004">{{cite journal | last=Pleuvry | first=Barbara J | title=Anxiolytics and hypnotics | journal=Anaesthesia & Intensive Care Medicine | volume=5 | issue=8 | date=2004 | doi=10.1383/anes.5.8.252.43294 | pages=252–256 | url=https://linkinghub.elsevier.com/retrieve/pii/S1472029906003511 | access-date=2 October 2025}}</ref>

===GABA<sub>A</sub> receptor agonists===
{{Main|GABAA receptor agonist}}

The [[GABAA receptor|GABA<sub>A</sub> receptor]] [[agonist]] [[gaboxadol]] (THIP; LU-2-030), a [[synthetic compound|synthetic]] [[chemical derivative|derivative]] of the [[neurotransmitter]] [[γ-aminobutyric acid]] (GABA) and an [[structural analog|analogue]] of the [[alkaloid]] [[muscimol]], underwent formal clinical development for the treatment of [[insomnia]] and reached [[Phases of clinical research#Phase III|phase 3]] [[clinical trial]]s for this indication in the 1990s and 2000s.<ref name="WaffordEbert2006">{{cite journal | vauthors = Wafford KA, Ebert B | title = Gaboxadol--a new awakening in sleep | journal = Curr Opin Pharmacol | volume = 6 | issue = 1 | pages = 30–36 | date = February 2006 | pmid = 16368265 | doi = 10.1016/j.coph.2005.10.004 | url = }}</ref><ref name="SorberaSilvestre2004">{{cite journal | author1=Sorbera, L.A. | author2=Castaner, J. | author3=Silvestre, J.S. | title=Gaboxadol | journal=Drugs of the Future | volume=29 | issue=5 | date=2004 | doi=10.1358/dof.2004.029.05.803754 | page=0449 | url=http://access.portico.org/stable?au=pjbf78x8shw | access-date=30 September 2025}}</ref><ref name="Morris2013">{{cite web | last=Morris | first=Hamilton | title=Gaboxadol, by Hamilton Morris | website=Harper&#039;s Magazine | date=2013 | url=https://harpers.org/archive/2013/08/gaboxadol/ | access-date=30 September 2025}}</ref> It was found to effectively improve [[sleep onset]] and [[sleep duration|duration]] in people with [[insomnia]].<ref name="WaffordEbert2006" /> In addition, and unlike other hypnotics like [[benzodiazepine]]s, gaboxadol improved [[slow wave sleep]], preserved [[sleep architecture]], and did not suppress [[REM sleep]].<ref name="WaffordEbert2006" /> Moreover, in contrast to [[benzodiazepine]]s, [[drug tolerance|tolerance]] did not appear to develop to gaboxadol's hypnotic effects.<ref name="WaffordEbert2006" />

The development of gaboxadol was discontinued in 2007.<ref name="Morris2013" /><ref name="Reuters2007">{{cite web | title=Merck, Lundbeck scrap insomnia drug after trials | website=Reuters | date=9 August 2007 | url=https://www.reuters.com/article/business/merck-lundbeck-scrap-insomnia-drug-after-trials-idUSN28285490/ | access-date=30 September 2025}}</ref><ref name="PharmaTimes2007">{{cite web | title=Merck & Co and Lundbeck's sleep drug terminated in Phase III | website=PharmaTimes | date=29 March 2007 | url=https://pharmatimes.com/news/merck_and_co_and_lundbecks_sleep_drug_terminated_in_phase_iii_989624/ | access-date=30 September 2025 | quote=The firms said they are discontinuing studies of the because data from recently-completed Phase III studies suggest that the overall clinical profile for gaboxadol in insomnia does not support further development. As a result of this new information, Merck and Lundbeck added that they will not file gaboxadol with the US Food and Drug Administration, or any other regulatory agencies worldwide, and are terminating the project.}}</ref> This was due to high rates of [[psychiatric disorder|psychiatric]] and [[hallucinogen]]ic effects in [[drug abuse|drug user]]s at supratherapeutic doses, failure of a 3-month efficacy trial, and other cited reasons.<ref name="Morris2013" /><ref name="Reuters2007" /><ref name="Lundbeck2007">https://web.archive.org/web/20071017080433/https://www.lundbeck.com/investor/Presentations/Teleconference/Teleconference_gaboxadol_20070328.pdf {{Bare URL PDF|date=November 2025}}</ref> Moreover, there was tension concerning hypnotics in the [[pharmaceutical industry]] at the time owing to bizarre reports of [[zolpidem]] (Ambien)-induced [[delirium]] that emerged in the media in 2006, which may have made the developer of gaboxadol more concerned about potential liability issues.<ref name="Morris2013" /> According to journalist [[Hamilton Morris]], the discontinuation of gaboxadol's late-stage development may have deprived people with insomnia access to an effective, safe, and non-addictive treatment.<ref name="Morris2013" /> There has been some further study of gaboxadol as a hypnotic by [[David Nutt]] and colleagues following the discontinuation of its development.<ref name="Nutt2025">{{cite journal | vauthors = Nutt DJ | title = Drug development in psychiatry: 50 years of failure and how to resuscitate it | journal = Lancet Psychiatry | volume = 12 | issue = 3 | pages = 228–238 | date = March 2025 | pmid = 39952266 | doi = 10.1016/S2215-0366(24)00370-5 | url = }}</ref><ref name="NuttWilsonLingford-Hughes2015">{{cite journal | vauthors = Nutt D, Wilson S, Lingford-Hughes A, Myers J, Papadopoulos A, Muthukumaraswamy S | title = Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: a study in healthy volunteers | journal = Neuropharmacology | volume = 88 | issue = | pages = 155–163 | date = January 2015 | pmid = 25195191 | doi = 10.1016/j.neuropharm.2014.08.017 | url = }}</ref>

[[Muscimol]], the compound from which gaboxadol was derived, is a [[natural product|naturally occurring]] constituent of ''[[Amanita]]'' mushrooms such as ''[[Amanita muscaria]]'' (fly agaric) and is a [[potency (pharmacology)|potent]] GABA<sub>A</sub> receptor agonist similarly.<ref name="Rivera-IllanesRecabarren-Gajardo2024">{{cite journal | vauthors = Rivera-Illanes D, Recabarren-Gajardo G | title = Classics in Chemical Neuroscience: Muscimol | journal = ACS Chem Neurosci | volume = 15 | issue = 18 | pages = 3257–3269 | date = September 2024 | pmid = 39254100 | doi = 10.1021/acschemneuro.4c00304 | url = }}</ref><ref name="Johnston2014" /> However, muscimol is less [[binding selectivity|selective]], more [[toxicity|toxic]], and far less-researched than gaboxadol.<ref name="Rivera-IllanesRecabarren-Gajardo2024" /><ref name="FrølundEbertKristiansen2002">{{cite journal | vauthors = Frølund B, Ebert B, Kristiansen U, Liljefors T, Krogsgaard-Larsen P | title = GABA(A) receptor ligands and their therapeutic potentials | journal = Curr Top Med Chem | volume = 2 | issue = 8 | pages = 817–832 | date = August 2002 | pmid = 12171573 | doi = 10.2174/1568026023393525 | quote = The fact that muscimol is a non-specific GABAA receptor agonist [38, 39], a substrate for the GABA-metabolizing enzyme, GABA transaminase [40], and moreover a neurotoxin, makes the compound therapeutically less valuable. [...] Further conformational restriction of the GABA structural element in muscimol has been achieved by incorporating the amino group into a piperidine ring leading to the bicyclic analogue, THIP, a specific GABAA agonist [11]. THIP has been shown to be devoid of the neurotoxic properties of muscimol and, in contrast to muscimol, is metabolically stable. }}</ref><ref name="Johnston2014" /><ref name="Morris2018-S02E07">{{cite episode | title = A Fungal Fairy Tale | issue = 7 | date = 9 January 2018 | credits = [[Hamilton Morris | Morris H]] | series = [[Hamilton's Pharmacopeia]] | season = 2 | url = https://www.youtube.com/watch?v=snM7RsUZtaE | publisher = [[Vice Media]] | network = [[Viceland]] }}</ref> Muscimol is reported to induce [[sleep]] in humans in addition to its well-known hallucinogenic effects that occur at sufficiently high doses.<ref name="Rivera-IllanesRecabarren-Gajardo2024" /><ref name="Stebelska2013">{{cite journal | vauthors = Stebelska K | title = Fungal hallucinogens psilocin, ibotenic acid, and muscimol: analytical methods and biologic activities | journal = Ther Drug Monit | volume = 35 | issue = 4 | pages = 420–442 | date = August 2013 | pmid = 23851905 | doi = 10.1097/FTD.0b013e31828741a5 }}</ref> The drug shows similar effects on sleep in rodents as gaboxadol.<ref name="KrogsgaardLarsenFrølundLiljefors2004">{{cite journal | vauthors = Krogsgaard-Larsen P, Frølund B, Liljefors T, Ebert B | title = GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic | journal = Biochem Pharmacol | volume = 68 | issue = 8 | pages = 1573–1580 | date = October 2004 | pmid = 15451401 | doi = 10.1016/j.bcp.2004.06.040 }}</ref><ref name="Johnston2014">{{cite journal | vauthors = Johnston GA | title = Muscimol as an ionotropic GABA receptor agonist | journal = Neurochem Res | volume = 39 | issue = 10 | pages = 1942–1947 | date = October 2014 | pmid = 24473816 | doi = 10.1007/s11064-014-1245-y | url = https://core.ac.uk/download/pdf/357370693.pdf | quote = We now know that muscimol is a potent agonist at GABAA receptors, a potent partial agonist at GABAC receptors and inactive at GABAB receptors. Unlike bicuculline and TPMPA, it does not distinguish between GABAA and GABAC receptors. It is a weak inhibitor/substrate of GABA uptake and not a substrate for GABA transaminase [18–21]. }}</ref><ref name="WaffordEbert2006" /> By the mid-2020s, [[microdosing]] of muscimol and ''Amanita'' mushrooms for claimed therapeutic benefits, the most prominently cited of which is improved sleep, has become increasingly prominent.<ref name="Rivera-IllanesRecabarren-Gajardo2024" /><ref name="SavickaitėLaubner-Sakalauskienė2025">{{cite journal | vauthors = Savickaitė E, Laubner-Sakalauskienė G | title = Emerging Risks of Amanita Muscaria: Case Reports on Increasing Consumption and Health Risks | journal = Acta Med Litu | volume = 32 | issue = 1 | pages = 182–189 | date = 2025 | pmid = 40641545 | pmc = 12239171 | doi = 10.15388/Amed.2025.32.1.23 }}</ref><ref name="HartwigKendrickAhmad2025">{{cite journal | vauthors = Hartwig J, Kendrick J, Ahmad G, Cook J, Matthews DB, Sharma P | title = Exploring User Experiences with Amanita muscaria: A Thematic Analysis of Reddit Online Forum Discussions | journal = Subst Use Misuse | volume = 60 | issue = 7 | pages = 952–961 | date = 2025 | pmid = 40057818 | doi = 10.1080/10826084.2025.2476141 | quote = The commonly reported reason for Amanita muscaria use was to improve sleep. }}</ref>

===GABA<sub>B</sub> receptor agonists===
The [[GABAB receptor|GABA<sub>B</sub> receptor]] [[agonist]] [[sodium oxybate]] (SXB; Xyrem), also known as [[γ-hydroxybutyrate]] (GHB), has hypnotic and sleep-improving effects.<ref name="Mayer2012">{{cite journal | vauthors = Mayer G | title = The use of sodium oxybate to treat narcolepsy | journal = Expert Rev Neurother | volume = 12 | issue = 5 | pages = 519–529 | date = May 2012 | pmid = 22550980 | doi = 10.1586/ern.12.42 | url = }}</ref><ref name="Swick2011">{{cite journal | vauthors = Swick TJ | title = Sodium oxybate: a potential new pharmacological option for the treatment of fibromyalgia syndrome | journal = Ther Adv Musculoskelet Dis | volume = 3 | issue = 4 | pages = 167–178 | date = August 2011 | pmid = 22870476 | pmc = 3382678 | doi = 10.1177/1759720X11411599 | url = | quote = In addition SXB has been shown to robustly increase slow wave sleep and decrease sleep fragmentation. Several large clinical trials have demonstrated SXB's ability to statistically improve pain, fatigue and a wide array of quality of life measurements of patients with fibromyalgia.}}</ref><ref name="Staud2011" /> It robustly increases [[slow wave sleep]] (deep sleep), decreases [[sleep fragmentation]], and improves [[rapid eye movement (REM) sleep]] consolidation, all whilst preserving physiological [[sleep architecture]].<ref name="Mayer2012" /><ref name="Swick2011" /><ref name="Staud2011" /><ref name="RothDauvilliersBogan2024" /> The drug is approved and clinically used in the treatment of [[narcolepsy]] and [[excessive daytime sleepiness]] (EDS).<ref name="Mayer2012" /><ref name="Broughton2015" /> Narcolepsy is associated with poor sleep, and sodium oxybate improves [[sleep quality]] and stability in the condition, in turn reducing symptoms like [[daytime sleepiness]] and [[cataplexy]].<ref name="Mayer2012" /><ref name="RothDauvilliersBogan2024">{{cite journal | vauthors = Roth T, Dauvilliers Y, Bogan RK, Plazzi G, Black J | title = Effects of oxybate dose and regimen on disrupted nighttime sleep and sleep architecture | journal = Sleep Med | volume = 114 | issue = | pages = 255–265 | date = February 2024 | pmid = 38244463 | doi = 10.1016/j.sleep.2023.12.015 | url = }}</ref> The robust enhancement of slow wave sleep by sodium oxybate is unusual and potentially advantageous relative to other hypnotics.<ref name="Dijk2010">{{cite journal | vauthors = Dijk DJ | title = Slow-wave sleep deficiency and enhancement: implications for insomnia and its management | journal = World J Biol Psychiatry | volume = 11 Suppl 1 | issue = | pages = 22–28 | date = June 2010 | pmid = 20509829 | doi = 10.3109/15622971003637645 | url = | quote = It is well established that benzodiazepines and to a lesser extent the Z-drugs, like zolpidem and zopiclone, suppress SWA and low-frequency EEG activity in the EEG during nonREM sleep and enhance high-frequency activity, in particular in the frequency range of sleep spindles (Lancel 1999). However, several compounds have been shown to increase SWS including, GAT-1 inhibitors, such as tiagabine (Mathias et al. 2001), GABA-A agonists such as gaboxadol, which bind to the extrasynaptic GABA-A receptor (Walsh et al. 2007; Dijk et al. 2009b), GABA-B modulators, such as GHB (Pardi and Black 2006) and 5HT 2A antagonists such as seganserin and eplivanserin (Dijk et al. 1989a; Landolt et al. 1999).}}</ref><ref name="Moldofsky2008" /><ref name="ZhangGruber2019">{{cite journal | vauthors = Zhang Y, Gruber R | title = Can Slow-Wave Sleep Enhancement Improve Memory? A Review of Current Approaches and Cognitive Outcomes | journal = Yale J Biol Med | volume = 92 | issue = 1 | pages = 63–80 | date = March 2019 | pmid = 30923474 | pmc = 6430170 | doi = | url = }}</ref> In addition, unlike the case of many other hypnotics, [[drug tolerance|tolerance]] does not appear to develop to the hypnotic effects of sodium oxybate.<ref name="Scharf2006">{{cite journal | vauthors = Scharf MB | title = Sodium oxybate for narcolepsy | journal = Expert Rev Neurother | volume = 6 | issue = 8 | pages = 1139–1146 | date = August 2006 | pmid = 16893342 | doi = 10.1586/14737175.6.8.1139 | url = }}</ref><ref name="Broughton2015" />

Sodium oxybate also completed formal clinical development for [[fibromyalgia]].<ref name="Staud2011">{{cite journal | vauthors = Staud R | title = Sodium oxybate for the treatment of fibromyalgia | journal = Expert Opin Pharmacother | volume = 12 | issue = 11 | pages = 1789–1798 | date = August 2011 | pmid = 21679091 | doi = 10.1517/14656566.2011.589836 | url = }}</ref><ref name="SpaethBennettBenson2012">{{cite journal | vauthors = Spaeth M, Bennett RM, Benson BA, Wang YG, Lai C, Choy EH | title = Sodium oxybate therapy provides multidimensional improvement in fibromyalgia: results of an international phase 3 trial | journal = Ann Rheum Dis | volume = 71 | issue = 6 | pages = 935–942 | date = June 2012 | pmid = 22294641 | pmc = 3371223 | doi = 10.1136/annrheumdis-2011-200418 | url = }}</ref> This condition has very high rates of [[non-restorative sleep]] (unrefreshing sleep) that may be directly involved in its symptoms.<ref name="WilkinsonShapiro2012">{{cite journal | vauthors = Wilkinson K, Shapiro C | title = Nonrestorative sleep: symptom or unique diagnostic entity? | journal = Sleep Med | volume = 13 | issue = 6 | pages = 561–569 | date = June 2012 | pmid = 22560828 | doi = 10.1016/j.sleep.2012.02.002 | url = }}</ref><ref name="StoneTaylorMcCrae2008">{{cite journal | vauthors = Stone KC, Taylor DJ, McCrae CS, Kalsekar A, Lichstein KL | title = Nonrestorative sleep | journal = Sleep Med Rev | volume = 12 | issue = 4 | pages = 275–288 | date = August 2008 | pmid = 18539057 | doi = 10.1016/j.smrv.2007.12.002 | url = }}</ref><ref name="Moldofsky2008">{{cite journal | vauthors = Moldofsky H | title = The significance, assessment, and management of nonrestorative sleep in fibromyalgia syndrome | journal = CNS Spectr | volume = 13 | issue = 3 Suppl 5 | pages = 22–26 | date = March 2008 | pmid = 18323770 | doi = 10.1017/s1092852900026808 | url = }}</ref><ref name="LeeAuger2024" /> Sodium oxybate improved sleep in fibromyalgia and showed moderate effectiveness in treating multiple symptoms across the condition including [[pain]] and [[fatigue]].<ref name="Staud2011" /> However, despite its effectiveness, sodium oxybate was ultimately not approved for treatment of fibromyalgia owing mostly to concerns about possible [[drug misuse|misuse]].<ref name="Staud2011" /> Sodium oxybate has also been investigated and been of interest to improve sleep and associated symptoms in other conditions with sleep disruption, such as [[myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS) and [[long COVID]], which also have high rates of non-restorative sleep.<ref name="Broughton2015">{{cite book | last=Broughton | first=Roger | title=Sleep Medicine | chapter=Gamma-Hydroxybutyrate (Sodium Oxybate): From the Initial Synthesis to the Treatment of Narcolepsy–Cataplexy and Beyond | publisher=Springer New York | publication-place=New York, NY | date=2015 | isbn=978-1-4939-2088-4 | doi=10.1007/978-1-4939-2089-1_63 | chapter-url=https://link.springer.com/10.1007/978-1-4939-2089-1_63 | access-date=29 September 2025 | pages=557–571}}</ref><ref name="LeeAuger2024">{{cite journal | last1=Lee | first1=Elliott K | last2=Auger | first2=R. Robert | title=Sleep and Long COVID—A Review and Exploration of Sleep Disturbances in Post Acute Sequelae of SARS-COV-2 (PASC) and Therapeutic Possibilities | journal=Current Sleep Medicine Reports | volume=10 | issue=2 | date=23 April 2024 | issn=2198-6401 | doi=10.1007/s40675-024-00299-4 | pages=169–180 | url=https://link.springer.com/10.1007/s40675-024-00299-4 | access-date=29 September 2025}}</ref><ref name="WilkinsonShapiro2012" /><ref name="SpitzerBroadman2010">{{cite journal | vauthors = Spitzer AR, Broadman M | title = Treatment of the narcoleptiform sleep disorder in chronic fatigue syndrome and fibromyalgia with sodium oxybate | journal = Pain Pract | volume = 10 | issue = 1 | pages = 54–59 | date = 2010 | pmid = 20629967 | doi = 10.1111/j.1533-2500.2009.00334.x | url = }}</ref> In addition, sodium oxybate was limitedly studied to improve [[insomnia]] in people with [[depression (mood)|depression]] or [[bipolar disorder]].<ref name="Broughton2015" /> However, it was reported to paradoxically disrupt sleep and induce narcolepsy-like changes in these individuals.<ref name="Broughton2015" /> Moreover, concerns about misuse have limited use of sodium oxybate for other medical conditions.<ref name="BusardoKiyriakouNapoletano2015">{{cite journal | vauthors = Busardò FP, Kyriakou C, Napoletano S, Marinelli E, Zaami S | title = Clinical applications of sodium oxybate (GHB): from narcolepsy to alcohol withdrawal syndrome | journal = Eur Rev Med Pharmacol Sci | volume = 19 | issue = 23 | pages = 4654–4563 | date = December 2015 | pmid = 26698265 | doi = | url = }}</ref> GHB has also garnered a reputation as a [[date rape|date-rape]] drug, although the actual prevalence of this appears to be much lower than popular perception.<ref name="FelmleeMorseMorris2021">{{cite journal | vauthors = Felmlee MA, Morse BL, Morris ME | title = γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology | journal = AAPS J | volume = 23 | issue = 1 | article-number = 22 | date = January 2021 | pmid = 33417072 | pmc = 8098080 | doi = 10.1208/s12248-020-00543-z | url = }}</ref>

The GABA<sub>B</sub> receptor agonist [[baclofen]] has also been more limitedly investigated for improvement of sleep and has been found to be effective in enhancing sleep similarly to sodium oxybate.<ref name="LeeAuger2024" /><ref name="BrownGuilleminault2011">{{cite journal | vauthors = Brown MA, Guilleminault C | title = A review of sodium oxybate and baclofen in the treatment of sleep disorders | journal = Curr Pharm Des | volume = 17 | issue = 15 | pages = 1430–1435 | date = 2011 | pmid = 21476957 | doi = 10.2174/138161211796197098 | url = }}</ref><ref name="WellendorphGaugerAndersen2025">{{cite journal | vauthors = Wellendorph P, Gauger SJ, Andersen JV, Kornum BR, Solbak SM, Frølund B | title = International Union of Basic and Clinical Pharmacology. CXX. γ-Hydroxybutyrate protein targets in the mammalian brain-beyond classic receptors | journal = Pharmacol Rev | volume = 77 | issue = 4 | article-number = 100064 | date = July 2025 | pmid = 40449125 | doi = 10.1016/j.pharmr.2025.100064 | url = }}</ref> However, in people with narcolepsy, baclofen and sodium oxybate both improved sleep but only sodium oxybate reduced daytime sleepiness.<ref name="WellendorphGaugerAndersen2025" /> In any case, research in this area is limited, and there remains significant interest in baclofen in the potential treatment of sleeping problems.<ref name="BrownGuilleminault2011" /><ref name="LeeAuger2024" /> Unlike sodium oxybate, baclofen is not a [[controlled substance]] and has much less or no [[misuse potential]].<ref name="WellendorphGaugerAndersen2025" /><ref name="KentParkLindsley2020" /> Baclofen and sodium oxybate have been found to activate the GABA<sub>B</sub> receptor differently, which is thought to underlie the differences in their effects.<ref name="WellendorphGaugerAndersen2025" /> Another difference between baclofen and sodium oxybate is that baclofen has a much longer [[elimination half-life]] and [[duration of action]] in comparison (half-life 3–4{{nbsp}}hours versus 0.5–1.0{{nbsp}}hours, respectively).<ref name="BrownGuilleminault2011" /><ref name="KothareKaleyias2010">{{cite journal | last1=Kothare | first1=Sanjeev V. | last2=Kaleyias | first2=Joseph | title=Pharmacotherapy of Narcolepsy: Focus on Sodium Oxybate | journal=Clinical Medicine Insights: Therapeutics | volume=2 | date=2010 | issn=1179-559X | doi=10.4137/CMT.S1087 | doi-access=free | article-number=CMT.S1087 }}</ref><ref name="KentParkLindsley2020">{{cite journal | vauthors = Kent CN, Park C, Lindsley CW | title = Classics in Chemical Neuroscience: Baclofen | journal = ACS Chem Neurosci | volume = 11 | issue = 12 | pages = 1740–1755 | date = June 2020 | pmid = 32436697 | doi = 10.1021/acschemneuro.0c00254 | url = }}</ref>

===GABA reuptake inhibitors===
{{Main|GABA reuptake inhibitor}}

The [[GABA transporter 1]] (GAT-1) and [[GABA reuptake inhibitor]] [[tiagabine]] (Gabitril) is approved and clinically used as an [[anticonvulsant]].<ref name="Walsh2009">{{cite journal | vauthors = Walsh JK | title = Enhancement of slow wave sleep: implications for insomnia | journal = J Clin Sleep Med | volume = 5 | issue = 2 Suppl | pages = S27–32 | date = April 2009 | pmid = 19998872 | pmc = 2824211 | doi = 10.5664/jcsm.5.2S.S27| url = }}</ref> It has also been used [[off-label use|off-label]] in the treatment of [[anxiety disorder]]s and other conditions.<ref name="SchwartzNihalani2006">{{cite journal | vauthors = Schwartz TL, Nihalani N | title = Tiagabine in anxiety disorders | journal = Expert Opin Pharmacother | volume = 7 | issue = 14 | pages = 1977–1987 | date = October 2006 | pmid = 17020423 | doi = 10.1517/14656566.7.14.1977 | url = }}</ref> The drug increases [[γ-aminobutyric acid]] (GABA) levels in the brain and has been found to improve sleep, including by increasing [[slow wave sleep]] (deep sleep).<ref name="Walsh2009" /><ref name="ZhangGruber2019" /> In addition, tiagabine has been reported to make sleep feel more restorative and to improve several cognitive outcomes.<ref name="Walsh2009" /><ref name="ZhangGruber2019" /> The drug has an [[elimination half-life]] of 5 to 8{{nbsp}}hours.<ref name="Brodie1995">{{cite journal | vauthors = Brodie MJ | title = Tiagabine pharmacology in profile | journal = Epilepsia | volume = 36 Suppl 6 | issue = | pages = S7–S9 | date = 1995 | pmid = 8595791 | doi = 10.1111/j.1528-1157.1995.tb06015.x | url = }}</ref>

=== Melatonin receptor agonists ===
{{Main|Melatonin receptor agonist}}

[[Melatonin (medication)|Melatonin]], the hormone produced in the [[pineal gland]] in the brain and secreted in dim light and darkness, among its other functions, promotes sleep in [[Diurnality|diurnal]] mammals.<ref>{{cite journal | vauthors = Arendt J, Skene DJ | title = Melatonin as a chronobiotic | journal = Sleep Medicine Reviews | volume = 9 | issue = 1 | pages = 25–39 | date = February 2005 | pmid = 15649736 | doi = 10.1016/j.smrv.2004.05.002 }}</ref> It activates the [[melatonin]] [[MT1 receptor|MT<sub>1</sub>]] and [[MT2 receptor|MT<sub>2</sub> receptor]]s to produce beneficial effects on sleep, therefore being used exogenously for mild insomnia.<ref>{{Cite journal |last1=Liu |first1=Jiabei |last2=Clough |first2=Shannon J. |last3=Hutchinson |first3=Anthony J. |last4=Adamah-Biassi |first4=Ekue B. |last5=Popovska-Gorevski |first5=Marina |last6=Dubocovich |first6=Margarita L. |date=2016 |title=MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective |journal=Annual Review of Pharmacology and Toxicology |volume=56 |pages=361–383 |doi=10.1146/annurev-pharmtox-010814-124742 |issn=1545-4304 |pmc=5091650 |pmid=26514204}}</ref> A small improvement in sleep onset and total sleep time by using melatonin has been shown in recent systematic reviews.<ref>{{Cite journal |last1=Low |first1=Tian Ling |last2=Choo |first2=Faith Nadine |last3=Tan |first3=Shian Ming |year=2020 |title=The efficacy of melatonin and melatonin agonists in insomnia - An umbrella review |journal=Journal of Psychiatric Research |volume=121 |pages=10–23 |doi=10.1016/j.jpsychires.2019.10.022 |issn=1879-1379 |pmid=31715492 |s2cid=207949129}}</ref> [[Synthetic compound|Synthetic]] [[structural analog|analogue]]s of melatonin, or [[melatonin receptor agonist]]s, have also been made. Among these, [[ramelteon]] and [[tasimelteon]] are used for sleep disorders. [[Agomelatine]] is an antidepressant of this class, with some studies also reporting an effect on sleep.<ref name="Williams2016">{{cite journal | vauthors = Williams WP, McLin DE, Dressman MA, Neubauer DN | title = Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders | journal = Pharmacotherapy | volume = 36 | issue = 9 | pages = 1028–41 | date = September 2016 | pmid = 27500861 | pmc = 5108473 | doi = 10.1002/phar.1822 | url = }}</ref>

=== Histamine H<sub>1</sub> receptor antagonists ===
{{Main|H1 antagonist}}

[[Antihistamine]]s, also known as [[histamine]] [[H1 receptor|H<sub>1</sub> receptor]] [[receptor antagonist|antagonist]]s, are a class of drugs that inhibit action at histamine H<sub>1</sub> receptors. They are clinically used to alleviate allergic reactions including [[allergic rhinitis]], [[allergic conjunctivitis]], and [[urticaria]], which are mediated by [[histamine]].{{Citation needed|date=March 2025}} [[First-generation antihistamine]]s, such as [[doxylamine]] (Unisom) and [[diphenhydramine]] (Benadryl), often cause sedation as a side effect, which can be utilized to treat insomnia. Some antihistamines, such as doxylamine, are available for purchase [[over-the-counter]] (OTC) in some countries and can be used for the occasional relief of insomnia.<ref>{{Cite journal |last1=Culpepper |first1=Larry |last2=Wingertzahn |first2=Mark A. |date=2015 |title=Over-the-Counter Agents for the Treatment of Occasional Disturbed Sleep or Transient Insomnia: A Systematic Review of Efficacy and Safety |journal=The Primary Care Companion for CNS Disorders |volume=17 |issue=6 |doi=10.4088/PCC.15r01798 |issn=2155-7772 |pmc=4805417 |pmid=27057416}}</ref> Many sedating antihistamines also have [[anticholinergic]] activity that can produce [[side effect]]s like [[cognitive impairment]].<ref name="VandeGriendAnderson2012" /><ref name="NerushShevyrinGolushko2024">{{cite journal | vauthors = Nerush MO, Shevyrin VA, Golushko NI, Moskalenko AM, Rosemberg DB, De Abreu MS, Yang LE, Galstyan DS, Lim LW, Demin KA, Kalueff AV | title = Classics in Chemical Neuroscience: Deliriant Antihistaminic Drugs | journal = ACS Chem Neurosci | volume = 15 | issue = 21 | pages = 3848–3862 | date = November 2024 | pmid = 39404616 | doi = 10.1021/acschemneuro.4c00505 | url = }}</ref> Low-dose [[doxepin]] (Silenor) is approved by the FDA for the treatment of insomnia.<ref name=":1">{{Cite web |title=Pharmacotherapy for insomnia in adults |url=https://www.uptodate.com/contents/pharmacotherapy-for-insomnia-in-adults |access-date=2023-03-13 |website=www.uptodate.com}}</ref> [[Binding selectivity|Non-selective]] hypnotics that possess histamine H<sub>1</sub> receptor antagonism include the [[antidepressant]]s [[amitriptyline]], high-dose [[doxepin]], [[trazodone]], and [[trimipramine]]; the [[antipsychotic]]s [[olanzapine]] and [[quetiapine]]; and the antihistamines [[hydroxyzine]], [[promethazine]], and [[cyproheptadine]], among others.<ref name="VandeGriendAnderson2012">{{cite journal | vauthors = Vande Griend JP, Anderson SL | title = Histamine-1 receptor antagonism for treatment of insomnia | journal = J Am Pharm Assoc (2003) | volume = 52 | issue = 6 | pages = e210–e219 | date = 2012 | pmid = 23229983 | doi = 10.1331/JAPhA.2012.12051 | url = }}</ref><ref name="VanGastel2022" /><ref name="EkambaramOwens2021">{{cite journal | vauthors = Ekambaram V, Owens J | title = Medications Used for Pediatric Insomnia | journal = Child Adolesc Psychiatr Clin N Am | volume = 30 | issue = 1 | pages = 85–99 | date = January 2021 | pmid = 33223070 | doi = 10.1016/j.chc.2020.09.001 | url = }}</ref><ref name="BadrNaguy2022">{{cite journal | vauthors = Badr B, Naguy A | title = Cyproheptadine: a psychopharmacological treasure trove? | journal = CNS Spectr | volume = 27 | issue = 5 | pages = 533–535 | date = October 2022 | pmid = 33632345 | doi = 10.1017/S1092852921000250 | url = }}</ref> [[Second-generation antihistamine]]s such as [[cetirizine]] and [[loratadine]] produce much less if any sedation due to a greatly reduced capacity to cross the [[blood–brain barrier]].<ref name="SlaterZechnichHaxby1999">{{Cite journal |last1=Slater |first1=J. W. |last2=Zechnich |first2=A. D. |last3=Haxby |first3=D. G. |year=1999 |title=Second-generation antihistamines: a comparative review |journal=Drugs |volume=57 |issue=1 |pages=31–47 |doi=10.2165/00003495-199957010-00004 |issn=0012-6667 |pmid=9951950 |s2cid=46984477}}</ref>

=== Orexin receptor antagonists ===
{{Main|Orexin antagonist}}

[[Orexin receptor antagonist]]s are drugs that block the [[orexin]] [[OX1 receptor|OX<sub>1</sub>]] and/or [[OX2 receptor|OX<sub>2</sub> receptor]]s, hence reducing the [[wakefulness-promoting agent|wakefulness-promoting effect]]s of the [[orexin system]] and inducing sleep.<ref>{{Cite journal |last1=Mieda |first1=Michihiro |last2=Tsujino |first2=Natsuko |last3=Sakurai |first3=Takeshi |date=2013 |title=Differential roles of orexin receptors in the regulation of sleep/wakefulness |journal=Frontiers in Endocrinology |volume=4 |page=57 |doi=10.3389/fendo.2013.00057 |issn=1664-2392 |pmc=3656340 |pmid=23730297 |doi-access=free}}</ref> [[Binding selectivity|Non-selective]] orexin receptor antagonists including [[suvorexant]], [[lemborexant]], and [[daridorexant]] and [[binding selectivity|selective]] orexin OX<sub>2</sub> receptor antagonists like [[seltorexant]] have been shown in [[clinical study|clinical studies]] to improve [[sleep onset]], [[sleep duration]], and [[sleep quality]].<ref name="KishiIkutaCitrome2025">{{cite journal | vauthors = Kishi T, Ikuta T, Citrome L, Sakuma K, Hatano M, Hamanaka S, Nishii Y, Iwata N | title = Comparative efficacy and safety of daridorexant, lemborexant, and suvorexant for insomnia: a systematic review and network meta-analysis | journal = Transl Psychiatry | volume = 15 | issue = 1 | article-number = 211 | date = June 2025 | pmid = 40555730 | pmc = 12187915 | doi = 10.1038/s41398-025-03439-8 | url = }}</ref><ref name="DeCrescenzoD'AloOstinelli2022" /><ref name="MesensKrystalMelkote2025">{{cite journal | vauthors = Mesens S, Krystal AD, Melkote R, Xu H, Pandina G, Saoud JB, Luthringer R, Savitz A, Drevets WC | title = Efficacy and Safety of Seltorexant in Insomnia Disorder: A Randomized Clinical Trial | journal = JAMA Psychiatry | volume = 82 | issue = 10 | pages = 967–976 | date = August 2025 | pmid = 40802194 | pmc = 12351464 | doi = 10.1001/jamapsychiatry.2025.1999 | url = }}</ref>

=== Serotonin 5-HT<sub>2A</sub> receptor antagonists ===
[[Serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] [[receptor antagonist|antagonist]]s such as [[ritanserin]], [[ketanserin]], [[eplivanserin]], [[volinanserin]], [[nelotanserin]], and [[pimavanserin]] have been studied and developed to improve sleep.<ref name="VanoverDavis2010">{{cite journal | vauthors = Vanover KE, Davis RE | title = Role of 5-HT2A receptor antagonists in the treatment of insomnia | journal = Nat Sci Sleep | volume = 2 | issue = | pages = 139–150 | date = 2010 | pmid = 23616706 | pmc = 3630942 | doi = 10.2147/nss.s6849 | doi-access = free | url = }}</ref><ref name="MontiTorteroloSpence2017">{{cite journal | last1=Monti | first1=Jaime M. | last2=Torterolo | first2=Pablo | last3=Spence | first3=David Warren | last4=Pandi-Perumal | first4=Seithikurippu R. | title=Selective Serotonin 5-HT2A Receptor Antagonists and Inverse Agonists Specifically Promote Slow Wave Sleep (Stage N3) in Man | journal=Sleep and Vigilance | volume=2 | issue=1 | date=6 November 2017 | issn=2510-2265 | doi=10.1007/s41782-017-0024-7 | pages=23–31 | url=https://link.springer.com/10.1007/s41782-017-0024-7 | access-date=30 September 2025}}</ref> They do not improve [[sleep onset]], but have been found to increase [[slow wave sleep]] (deep sleep) and reduce [[nighttime awakening]]s.<ref name="VanoverDavis2010" /><ref name="MontiTorteroloSpence2017" /> Conversely, improvement in subjective sleep ratings have been more mixed.<ref name="VanoverDavis2010" /> Ultimately no [[binding selectivity|selective]] serotonin 5-HT<sub>2A</sub> receptor antagonists have been approved for treatment of [[insomnia]].<ref name="VanoverDavis2010" /> The only selective serotonin 5-HT<sub>2A</sub> receptor antagonist to be approved for any indication is pimavanserin for treatment of [[Parkinson's disease]] [[psychosis]].<ref name="MontiTorteroloSpence2017" /> Besides selective serotonin 5-HT<sub>2A</sub> receptor antagonists however, many non-selective agents used as hypnotics show serotonin 5-HT<sub>2A</sub> receptor antagonism, for instance [[antidepressant]]s like [[trazodone]], [[mirtazapine]], and [[amitriptyline]], [[antipsychotic]]s like [[quetiapine]] and [[olanzapine]], and [[antihistamine]]s like [[hydroxyzine]] and [[cyproheptadine]].<ref name="SchwartzGoradia2013">{{cite journal | vauthors = Schwartz TL, Goradia V | title = Managing insomnia: an overview of insomnia and pharmacologic treatment strategies in use and on the horizon | journal = Drugs Context | volume = 2013 | issue = | article-number = 212257 | date = October 2013 | pmid = 24432044 | pmc = 3884958 | doi = 10.7573/dic.212257 | url = }}</ref><ref name="DeMartinisWinokur2007">{{cite journal | vauthors = DeMartinis NA, Winokur A | title = Effects of psychiatric medications on sleep and sleep disorders | journal = CNS Neurol Disord Drug Targets | volume = 6 | issue = 1 | pages = 17–29 | date = February 2007 | pmid = 17305551 | doi = 10.2174/187152707779940835 | url = }}</ref><ref name="DujardinPijpersPevernagie2022">{{cite journal | vauthors = Dujardin S, Pijpers A, Pevernagie D | title = Prescription Drugs Used in Insomnia | journal = Sleep Med Clin | volume = 17 | issue = 3 | pages = 315–328 | date = September 2022 | pmid = 36150797 | doi = 10.1016/j.jsmc.2022.06.001 | url = }}</ref><ref name="VanGastel2022">{{cite journal | vauthors = Van Gastel A | title = Drug-Induced Insomnia and Excessive Sleepiness | journal = Sleep Med Clin | volume = 17 | issue = 3 | pages = 471–484 | date = September 2022 | pmid = 36150808 | doi = 10.1016/j.jsmc.2022.06.011 | url = }}</ref><ref name="NerushShevyrinGolushko2024" />

=== Gabapentinoids ===
{{Main|Gabapentinoid}}

[[Gabapentinoid]]s, also known as [[CACNA2D1|α<sub>2</sub>δ subunit]]-containing [[voltage-gated calcium channel]] [[ligand (biochemistry)|ligand]]s, include drugs like [[gabapentin]], [[pregabalin]], and [[gabapentin enacarbil]].<ref name="AthavaleMurnion2023">{{cite journal | vauthors = Athavale A, Murnion B | title = Gabapentinoids: a therapeutic review | journal = Aust Prescr | volume = 46 | issue = 4 | pages = 80–85 | date = December 2023 | pmid = 38152314 | pmc = 10751078 | doi = 10.18773/austprescr.2023.025 | url = }}</ref> They have been found to increase [[slow wave sleep]] (deep sleep) in people with [[insomnia]] and healthy individuals.<ref name="AtkinComaiGobbi2018">{{cite journal | vauthors = Atkin T, Comai S, Gobbi G | title = Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery | journal = Pharmacol Rev | volume = 70 | issue = 2 | pages = 197–245 | date = April 2018 | pmid = 29487083 | doi = 10.1124/pr.117.014381 | url = }}</ref><ref name="DeMartinisWinokur2007" /> However, they do not appear to improve [[sleep onset]].<ref name="AtkinComaiGobbi2018" /> The gabapentinoid [[atagabalin]] (PD-0200390) was under formal development for treatment of insomnia, but development was discontinued following unsatisfactory clinical trial results.<ref name="AtkinComaiGobbi2018" /> [[PD-0299685]] is another gabapentinoid that was under development for the treatment of insomnia, specifically that related to [[menopausal symptoms]], but its development was discontinued similarly.<ref name="Lewis2009">{{cite journal | vauthors = Lewis V | title = Undertreatment of menopausal symptoms and novel options for comprehensive management | journal = Curr Med Res Opin | volume = 25 | issue = 11 | pages = 2689–2698 | date = November 2009 | pmid = 19775194 | doi = 10.1185/03007990903240519 | url = | quote = PD-299685: A nonhormonal agent related to the alpha-2-delta receptor binding, PD-299685, is currently under development for the treatment of menopausal hot flushes and insomnia.}}</ref><ref name="AdisInsight-PD-0299685">{{cite web | title=PD 0299685 | website=AdisInsight | date=5 November 2023 | url=https://adisinsight.springer.com/drugs/800021998 | access-date=3 October 2025}}</ref>

=== Cannabinoids ===
{{Main|Cannabinoid|Cannabis (drug)}}

[[Cannabinoid]]s, or [[cannabinoid receptor]] [[agonist]]s, such as the [[tetrahydrocannabinol|δ<sup>9</sup>-tetrahydrocannabinol]] (THC) found in [[cannabis (drug)|cannabis]], have been found to be effective in improving sleep in healthy people and in people with [[insomnia]].<ref name="daSilvaBarbosadeLima2025">{{cite journal | vauthors = da Silva GH, Barbosa EC, de Lima FR, Barroso DC, Paez LE, Guimarães FB, Lança SB, de Faria SB, Petrucci AB, Garbacka A, Walsh JH | title = Effectiveness of cannabinoids on subjective sleep quality in people with and without insomnia or poor sleep: A systematic review and meta-analysis of randomised studies | journal = Sleep Med Rev | volume = 84 | issue = | article-number = 102156 | date = August 2025 | pmid = 40929927 | doi = 10.1016/j.smrv.2025.102156 | url = }}</ref><ref name="LavenderMcGregorSuraev2022" /> They have been found to improve [[sleep onset]], [[total sleep time|sleep duration]], and [[sleep quality]].<ref name="daSilvaBarbosadeLima2025" /><ref name="LavenderMcGregorSuraev2022">{{cite journal | vauthors = Lavender I, McGregor IS, Suraev A, Grunstein RR, Hoyos CM | title = Cannabinoids, Insomnia, and Other Sleep Disorders | journal = Chest | volume = 162 | issue = 2 | pages = 452–465 | date = August 2022 | pmid = 35537535 | doi = 10.1016/j.chest.2022.04.151 | quote = The most robustly designed study to date examined the safety and efficacy of the cannabinoid formulation ZTL101 (D9-THC 10 mg, CBN 1 mg, and CBD 0.5 mg) relative to placebo in a sample of 23 patients with chronic insomnia disorder.11 Participants self-administered ZTL-101 one hour prior to bedtime for 2 weeks, with the option to double the dose after the fourth night (52% of participants increased the dose). ZTL-101 improved subjective sleep quality by 5.1 points (95% CI, –7.3 to –2.9) on the Insomnia Severity Index and improved self-reported sleep-onset latency, total sleep time, subjective sleep quality, and feelings of rest upon waking. Actigraphy measures indicated reduced wake following sleep onset and increased total sleep time; however, no differences in polysomnography indexes were observed.11 Headaches, xerostomia, dizziness, and "feeling abnormal" were reported more frequently with active treatment (n = 17) than with placebo (n = 4), but these adverse events were self-limiting and did not persist upon wake. }}</ref> [[Cannabidiol]] (CBD), which acts differently than other cannabinoids like THC, is not effective in improving sleep on the other hand.<ref name="daSilvaBarbosadeLima2025" /> [[Zenivol]] is a [[cannabis extract]] which is approved for the treatment of insomnia in [[Germany]].<ref name="AdisInsight-Zenivol">{{cite web | title = Cannabidiol/tetrahydrocannabinol | date = 25 July 2022 | website = AdisInsight | url = https://adisinsight.springer.com/drugs/800057418 | access-date = 1 October 2025 }}</ref><ref name="LavenderMcGregorSuraev2022" />

===α<sub>1</sub>- and β-adrenergic receptor antagonists===
{{Main|Alpha-1 blocker|Beta blocker}}

The [[alpha-1 adrenergic receptor|α<sub>1</sub>-adrenergic receptor]] [[receptor antagonist|antagonist]] [[prazosin]] is used [[off-label use|off-label]] to treat [[insomnia]], [[nightmare]]s, and poor [[sleep quality]] in people with [[post-traumatic stress disorder]] (PTSD).<ref name="Krystal2015">{{cite journal | vauthors = Krystal AD | title = New Developments in Insomnia Medications of Relevance to Mental Health Disorders | journal = Psychiatr Clin North Am | volume = 38 | issue = 4 | pages = 843–860 | date = December 2015 | pmid = 26600112 | pmc = 5972036 | doi = 10.1016/j.psc.2015.08.001 | url = }}</ref><ref name="MendesPereiraCoutinho2025">{{cite journal | vauthors = Mendes TP, Pereira BG, Coutinho ES, Melani MS, Neylan TC, Berger W | title = Factors impacting prazosin efficacy for nightmares and insomnia in PTSD patients - a systematic review and meta-regression analysis | journal = Prog Neuropsychopharmacol Biol Psychiatry | volume = 136 | issue = | article-number = 111253 | date = January 2025 | pmid = 39828080 | doi = 10.1016/j.pnpbp.2025.111253 | url = }}</ref><ref name="LappasGlarouPolyzopoulou2024">{{cite journal | vauthors = Lappas AS, Glarou E, Polyzopoulou ZA, Goss G, Huhn M, Samara MT, Christodoulou NG | title = Pharmacotherapy for sleep disturbances in post-traumatic stress disorder (PTSD): A network meta-analysis | journal = Sleep Med | volume = 119 | issue = | pages = 467–479 | date = July 2024 | pmid = 38795401 | doi = 10.1016/j.sleep.2024.05.032 | url = }}</ref><ref name="MaherRegoAsnis2006">{{cite journal | vauthors = Maher MJ, Rego SA, Asnis GM | title = Sleep disturbances in patients with post-traumatic stress disorder: epidemiology, impact and approaches to management | journal = CNS Drugs | volume = 20 | issue = 7 | pages = 567–590 | date = 2006 | pmid = 16800716 | doi = 10.2165/00023210-200620070-00003 | url = }}</ref> It is clinically effective for this purpose.<ref name="MendesPereiraCoutinho2025" /><ref name="LappasGlarouPolyzopoulou2024" /><ref name="MaherRegoAsnis2006" /> However, the drug is also an [[antihypertensive agent]] and can lower [[blood pressure]], thereby producing [[side effect]]s like [[dizziness]] and [[orthostatic hypotension]].<ref name="Krystal2015" /> Certain [[binding selectivity|non-selective]] hypnotics such as [[trazodone]] and [[tricyclic antidepressant]]s (TCAs) like [[amitriptyline]] and [[trimipramine]] are also α<sub>1</sub>-adrenergic receptor antagonists.<ref name="AtkinComaiGobbi2018" /><ref name="Feighner1999">{{cite journal | vauthors = Feighner JP | title = Mechanism of action of antidepressant medications | journal = J Clin Psychiatry | volume = 60 Suppl 4 | issue = | pages = 4–11; discussion 12–3 | date = 1999 | pmid = 10086478 | doi = | url = }}</ref><ref name="EverittBaldwinStuart2018">{{cite journal | vauthors = Everitt H, Baldwin DS, Stuart B, Lipinska G, Mayers A, Malizia AL, Manson CC, Wilson S | title = Antidepressants for insomnia in adults | journal = Cochrane Database Syst Rev | volume = 2018 | issue = 5 | article-number = CD010753 | date = May 2018 | pmid = 29761479 | pmc = 6494576 | doi = 10.1002/14651858.CD010753.pub2 | url = }}</ref> The combination of prazosin and the [[central nervous system|centrally-penetrant]] [[beta blocker]] (β-adrenergic receptor antagonist) [[timolol]] has been found to be synergistic in producing sedative and hypnotic effects in animals.<ref name="AtkinComaiGobbi2018" /><ref name="BerridgeEspaña2000">{{cite journal | vauthors = Berridge CW, España RA | title = Synergistic sedative effects of noradrenergic alpha(1)- and beta-receptor blockade on forebrain electroencephalographic and behavioral indices | journal = Neuroscience | volume = 99 | issue = 3 | pages = 495–505 | date = 2000 | pmid = 11029541 | doi = 10.1016/s0306-4522(00)00215-3 | url = }}</ref> Conversely, timolol alone produced no such effects.<ref name="AtkinComaiGobbi2018" /><ref name="BerridgeEspaña2000" /> Centrally active beta blockers like [[propranolol]] and [[metoprolol]] on their own are not effective or clinically used as hypnotics and have actually been associated with insomnia as a side effect.<ref name="EddinPreyraAhmadi2025">{{cite journal | vauthors = Eddin LE, Preyra R, Ahmadi F, Jafari A, Omrani MA, Muanda FT | title = β-Blockers and risk of neuropsychiatric disorders: A systematic review and meta-analysis | journal = Br J Clin Pharmacol | volume = 91 | issue = 2 | pages = 325–337 | date = February 2025 | pmid = 39658346 | pmc = 11773113 | doi = 10.1111/bcp.16361 | url = }}</ref><ref name="CojocariuMaștaleruSascău2021">{{cite journal | vauthors = Cojocariu SA, Maștaleru A, Sascău RA, Stătescu C, Mitu F, Leon-Constantin MM | title = Neuropsychiatric Consequences of Lipophilic Beta-Blockers | journal = Medicina (Kaunas) | volume = 57 | issue = 2 | date = February 2021 | page = 155 | pmid = 33572109 | pmc = 7914867 | doi = 10.3390/medicina57020155 | doi-access = free | url = }}</ref><ref name="DanjouPuechWarot1987">{{cite journal | vauthors = Danjou P, Puech A, Warot D, Benoit JF | title = Lack of sleep-inducing properties of propranolol (80 mg) in chronic insomniacs previously treated by common hypnotic medications | journal = Int Clin Psychopharmacol | volume = 2 | issue = 2 | pages = 135–140 | date = April 1987 | pmid = 3298418 | doi = 10.1097/00004850-198704000-00007 | url = }}</ref> Certain beta blockers like [[labetalol]] and [[carvedilol]] also block the α<sub>1</sub>-adrenergic receptor to varying extents and have been associated with [[somnolence]] as a side effect.<ref name="VanGastel2022" /><ref name="RichardsHollanderRamoska2017">{{cite journal | vauthors = Richards JR, Hollander JE, Ramoska EA, Fareed FN, Sand IC, Izquierdo Gómez MM, Lange RA | title = β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon | journal = J Cardiovasc Pharmacol Ther | volume = 22 | issue = 3 | pages = 239–249 | date = May 2017 | pmid = 28399647 | doi = 10.1177/1074248416681644 | url = }}</ref><ref name="PagelPandi-PerumalMonti2018">{{cite journal | last1=Pagel | first1=J. F. | last2=Pandi-Perumal | first2=Seithikurippu R. | last3=Monti | first3=Jaime M. | title=Treating insomnia with medications | journal=Sleep Science and Practice | volume=2 | issue=1 | date=2018 | issn=2398-2683 | doi=10.1186/s41606-018-0025-z | doi-access=free | article-number=5 | quote=The complaints of tiredness, fatigue and daytime sleepiness (2–4.3%) associated with beta-blocker use may occur secondary to disturbed sleep or direct action of the drug. Beta-blocking drugs with vasodilating properties (e.g. carvedilol, labetalol) are also associated with reported fatigue and somnolence (3–11%). [...] Prazosin, a norepinephine antagonist, has demonstrated value in treating insomnia associated with PTSD nightmares (Raskind et al. 2003). Clonidine is sometimes utilized to treat the agitation and insomnia that result from using amphetamines to treat AD/HD in pediatric patients (Ming et al. 2011).}}</ref> However, these two beta blockers have also been associated with insomnia similarly to selective beta blockers.<ref name="VanGastel2022" />

===α<sub>2</sub>-Adrenergic receptor agonists===
[[Alpha-2 adrenergic receptor|α<sub>2</sub>-Adrenergic receptor]] [[agonist]]s like [[clonidine]] can improve sleep and may be useful in the treatment of insomnia.<ref name="AtkinComaiGobbi2018" /><ref name="AnandTongBesag2017">{{cite journal | vauthors = Anand S, Tong H, Besag FM, Chan EW, Cortese S, Wong IC | title = Safety, Tolerability and Efficacy of Drugs for Treating Behavioural Insomnia in Children with Attention-Deficit/Hyperactivity Disorder: A Systematic Review with Methodological Quality Assessment | journal = Paediatr Drugs | volume = 19 | issue = 3 | pages = 235–250 | date = June 2017 | pmid = 28391425 | doi = 10.1007/s40272-017-0224-6 | url = }}</ref><ref name="MammarellaRandazzoRomano2025">{{cite journal | vauthors = Mammarella V, Randazzo L, Romano S, Breda M, Bruni O | title = Pharmacological management for insomnia in children and adolescents with autism and attention deficit and hyperactivity disorder | journal = Expert Opin Pharmacother | volume = 26 | issue = 9 | pages = 1079–1098 | date = June 2025 | pmid = 40400273 | doi = 10.1080/14656566.2025.2508277 | url = }}</ref> An example of this is in the treatment of insomnia in children and adolescents with [[attention deficit hyperactivity disorder]] (ADHD), for instance due [[psychostimulant|stimulant]] therapy.<ref name="AnandTongBesag2017" /><ref name="MammarellaRandazzoRomano2025" /><ref name="NguyenTharaniRahmani2014">{{cite journal | vauthors = Nguyen M, Tharani S, Rahmani M, Shapiro M | title = A review of the use of clonidine as a sleep aid in the child and adolescent population | journal = Clin Pediatr (Phila) | volume = 53 | issue = 3 | pages = 211–216 | date = March 2014 | pmid = 24027233 | doi = 10.1177/0009922813502123 | url = }}</ref> Similarly to clonidine, the α<sub>2</sub>-adrenergic receptor agonist [[dexmedetomidine]] has sedative and hypnotic effects and is used to produce [[sedation]] in hospital settings.<ref name="WeerinkStruysHannivoort2017">{{cite journal | vauthors = Weerink MA, Struys MM, Hannivoort LN, Barends CR, Absalom AR, Colin P | title = Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine | journal = Clin Pharmacokinet | volume = 56 | issue = 8 | pages = 893–913 | date = August 2017 | pmid = 28105598 | pmc = 5511603 | doi = 10.1007/s40262-017-0507-7 | url = }}</ref> The sleep induced by dexmedetomidine is said to closely resemble natural sleep.<ref name="WeerinkStruysHannivoort2017">{{cite journal | vauthors = Weerink MA, Struys MM, Hannivoort LN, Barends CR, Absalom AR, Colin P | title = Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine | journal = Clin Pharmacokinet | volume = 56 | issue = 8 | pages = 893–913 | date = August 2017 | pmid = 28105598 | pmc = 5511603 | doi = 10.1007/s40262-017-0507-7 | url = }}</ref><ref name="Nelson_2003">{{cite journal | vauthors = Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M | title = The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects | journal = Anesthesiology | volume = 98 | issue = 2 | pages = 428–436 | date = February 2003 | pmid = 12552203 | doi = 10.1097/00000542-200302000-00024 | s2cid = 5034487 | doi-access = free }}</ref><ref name="HuupponenMaksimowLapinlampi2008">{{cite journal | vauthors = Huupponen E, Maksimow A, Lapinlampi P, Särkelä M, Saastamoinen A, Snapir A, Scheinin H, Scheinin M, Meriläinen P, Himanen SL, Jääskeläinen S | display-authors = 6 | title = Electroencephalogram spindle activity during dexmedetomidine sedation and physiological sleep | journal = Acta Anaesthesiologica Scandinavica | volume = 52 | issue = 2 | pages = 289–294 | date = February 2008 | pmid = 18005372 | doi = 10.1111/j.1399-6576.2007.01537.x | s2cid = 34923432 }}</ref> The [[binding selectivity|selective]] [[alpha-2A adrenergic receptor|α<sub>2A</sub>-adrenergic receptor]] agonist [[tasipimidine]] (ODM-105) is under development for the treatment of insomnia and is in [[Phases of clinical research#Phase II|phase 2]] [[clinical trial]]s for this indication as of October 2024.<ref name="LehtimäkiJalavaUnkila2022">{{cite journal | vauthors = Lehtimäki J, Jalava N, Unkila K, Aspegren J, Haapalinna A, Pesonen U | title = Tasipimidine-the pharmacological profile of a novel orally active selective α2A-adrenoceptor agonist | journal = Eur J Pharmacol | volume = 923 | issue = | article-number = 174949 | date = May 2022 | pmid = 35405115 | doi = 10.1016/j.ejphar.2022.174949 | url = }}</ref><ref name="AdisInsight-Tasipimidine">{{cite web | title=Tasipimidine | website=AdisInsight | date=28 October 2024 | url=https://adisinsight.springer.com/drugs/800070674 | access-date=2 October 2025}}</ref> α<sub>2</sub>-Adrenergic receptor agonists can produce [[hypotension]] and [[bradycardia]] as [[side effect]]s, which has limited their use.<ref name="KhanFergusonJones1999">{{cite journal | vauthors = Khan ZP, Ferguson CN, Jones RM | title = alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role | journal = Anaesthesia | volume = 54 | issue = 2 | pages = 146–165 | date = February 1999 | pmid = 10215710 | doi = 10.1046/j.1365-2044.1999.00659.x | url = }}</ref><ref name="WeerinkStruysHannivoort2017" /> Activation of the α<sub>2A</sub>-adrenergic receptor is thought to be responsible for most of the physiological effects of the α<sub>2</sub>-adrenergic receptors, including hypotension.<ref name="LehtimäkiJalavaUnkila2022" /> On the other hand, the preferential α<sub>2A</sub>-adrenergic receptor agonist [[guanfacine]] appears to show less sedation and hypotension than clonidine.<ref name="ArnstenJin2012">{{cite journal | vauthors = Arnsten AF, Jin LE | title = Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale | journal = Yale J Biol Med | volume = 85 | issue = 1 | pages = 45–58 | date = March 2012 | pmid = 22461743 | pmc = 3313539 | doi = | url = }}</ref>

===Serotonin precursors===
The [[serotonin precursor]]s [[tryptophan]] and [[5-hydroxytryptophan]] (5-HTP; oxitriptan) are available as [[over-the-counter drug|over-the-counter]] [[dietary supplement|supplement]]s.<ref name="MeolieRosenKristo2005">{{cite journal | vauthors = Meolie AL, Rosen C, Kristo D, Kohrman M, Gooneratne N, Aguillard RN, Fayle R, Troell R, Townsend D, Claman D, Hoban T, Mahowald M | title = Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence | journal = J Clin Sleep Med | volume = 1 | issue = 2 | pages = 173–187 | date = April 2005 | pmid = 17561634 | doi = 10.5664/jcsm.26314| url = }}</ref><ref name="Boman1988">{{cite journal | vauthors = Boman B | title = L-tryptophan: a rational anti-depressant and a natural hypnotic? | journal = Aust N Z J Psychiatry | volume = 22 | issue = 1 | pages = 83–97 | date = March 1988 | pmid = 3285826 | doi = 10.1080/00048678809158946 | url = }}</ref> They are often used to produce [[sleepiness]] and treat [[insomnia]].<ref name="MeolieRosenKristo2005" /><ref name="Boman1988" /> However, little to no clinical data exist to support their use or effectiveness.<ref name="MeolieRosenKristo2005" />

===Multiple mechanisms===
====Antidepressants====
Some [[antidepressant]]s have hypnotic and/or sedative effects.<ref name="AtkinComaiGobbi2018" /> These include the [[serotonin antagonist and reuptake inhibitor]] (SARI) [[trazodone]],<ref>{{cite journal | vauthors = Haria M, Fitton A, McTavish D | title = Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders | journal = Drugs & Aging | volume = 4 | issue = 4 | pages = 331–355 | date = April 1994 | pmid = 8019056 | doi = 10.2165/00002512-199404040-00006 | s2cid = 265772823 }}</ref> [[tricyclic antidepressant]]s (TCAs) such as [[amitriptyline]],<ref>{{cite web|title=Levate (amitriptyline), dosing, indications, interactions, adverse effects, and more |work=Medscape Reference |publisher=WebMD |access-date=1 December 2013 |url=http://reference.medscape.com/drug/levate-amitriptyline-342936#showall}}</ref> [[doxepin]],<ref>{{cite journal | vauthors = Hajak G, Rodenbeck A, Voderholzer U, Riemann D, Cohrs S, Hohagen F, Berger M, Rüther E | display-authors = 6 | title = Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study | journal = The Journal of Clinical Psychiatry | volume = 62 | issue = 6 | pages = 453–463 | date = June 2001 | pmid = 11465523 | doi = 10.4088/JCP.v62n0609 }}</ref> and [[trimipramine]],<ref>{{cite book | isbn = 978-0-85711-084-8 | title = British National Formulary (BNF) | last1 = Joint Formulary Committee | year = 2013 | publisher = Pharmaceutical Press | location = London, UK | edition = 65 | url-access = registration | url = https://archive.org/details/bnf65britishnati0000unse }} {{page needed|date=February 2014}}</ref> and [[tetracyclic antidepressant]]s (TeCAs) like [[mirtazapine]]<ref>{{cite journal | vauthors = Hartmann PM | title = Mirtazapine: a newer antidepressant | journal = American Family Physician | volume = 59 | issue = 1 | pages = 159–161 | date = January 1999 | pmid = 9917581 }}</ref><ref>{{cite journal | vauthors = Jindal RD | title = Insomnia in patients with depression: some pathophysiological and treatment considerations | journal = CNS Drugs | volume = 23 | issue = 4 | pages = 309–329 | year = 2009 | pmid = 19374460 | doi = 10.2165/00023210-200923040-00004 | s2cid = 22052011 }}</ref> and [[mianserin]].<ref>{{cite journal | vauthors = Wakeling A | title = Efficacy and side effects of mianserin, a tetracyclic antidepressant | journal = Postgraduate Medical Journal | volume = 59 | issue = 690 | pages = 229–231 | date = April 1983 | pmid = 6346303 | pmc = 2417496 | doi = 10.1136/pgmj.59.690.229 }}</ref><ref name="AtkinComaiGobbi2018" /> These agents produce their hypnotic and sedative effects via multiple [[mechanism of action|mechanisms of action]] that may include [[histamine]] [[H1 receptor|H<sub>1</sub> receptor]] [[receptor antagonist|antagonism]], [[serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] antagonism, and [[alpha-1 adrenergic receptor|α<sub>1</sub>-adrenergic receptor]] antagonism.<ref name="AtkinComaiGobbi2018" /> Some hypnotic antidepressants, such as trazodone and mirtazapine, have been shown to enhance [[slow wave sleep]], which may be due to serotonin 5-HT<sub>2A</sub> receptor antagonism.<ref name="Walsh2009" />

====Antipsychotics====
Certain [[typical antipsychotic]]s (first-generation) like [[chlorpromazine]] and [[atypical antipsychotic]]s (second-generation) including [[clozapine]], [[olanzapine]], [[quetiapine]], [[risperidone]], [[ziprasidone]], and [[zotepine]] may have sedative and/or hypnotic effects and have been used in the treatment of insomnia.<ref name="FangSunWang2016">{{cite journal | vauthors = Fang F, Sun H, Wang Z, Ren M, Calabrese JR, Gao K | title = Antipsychotic Drug-Induced Somnolence: Incidence, Mechanisms, and Management | journal = CNS Drugs | volume = 30 | issue = 9 | pages = 845–867 | date = September 2016 | pmid = 27372312 | doi = 10.1007/s40263-016-0352-5 | url = }}</ref><ref>{{cite journal | vauthors = Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM | display-authors = 6 | title = Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis | journal = Lancet | volume = 382 | issue = 9896 | pages = 951–962 | date = September 2013 | pmid = 23810019 | doi = 10.1016/S0140-6736(13)60733-3 | s2cid = 32085212 }}</ref> However, the most commonly used agents for insomnia are quetiapine and olanzapine.<ref name="AtkinComaiGobbi2018" /><ref name="Modesto-LoweHarabaszWalker2021">{{cite journal | vauthors = Modesto-Lowe V, Harabasz AK, Walker SA | title = Quetiapine for primary insomnia: Consider the risks | journal = Cleve Clin J Med | volume = 88 | issue = 5 | pages = 286–294 | date = May 2021 | pmid = 33941603 | doi = 10.3949/ccjm.88a.20031 | url = }}</ref> They are thought to produce these effects via multiple [[mechanism of action|mechanisms of action]], including [[histamine]] [[H1 receptor|H<sub>1</sub> receptor]] [[receptor antagonist|antagonism]], [[serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] antagonism, [[alpha-1 adrenergic receptor|α<sub>1</sub>-adrenergic receptor]] antagonism, and/or [[dopamine]] [[D2 receptor|D<sub>2</sub> receptor]] antagonism.<ref name="AtkinComaiGobbi2018" /><ref name="FangSunWang2016" /> While some of these drugs are frequently prescribed for insomnia, such use is not recommended unless the insomnia is due to an underlying mental health condition treatable by [[antipsychotic]]s as the risks frequently outweigh the benefits.<ref name="Off-Label Use">{{cite book |title=Off-Label Use of Atypical Antipsychotics: An Update |vauthors=Maglione M, Maher AR, Hu J, Wang Z, Shanman R, Shekelle PG, Roth B, Hilton L, Suttorp MJ |publisher=Agency for Healthcare Research and Quality |year=2011 |series=Comparative Effectiveness Reviews, No. 43 |location=Rockville |pmid=22973576}}</ref><ref>{{cite journal | vauthors = Coe HV, Hong IS | title = Safety of low doses of quetiapine when used for insomnia | journal = The Annals of Pharmacotherapy | volume = 46 | issue = 5 | pages = 718–722 | date = May 2012 | pmid = 22510671 | doi = 10.1345/aph.1Q697 | s2cid = 9888209 }}</ref> Some of the more serious adverse effects have been observed to occur at the low doses used for this off-label prescribing, such as [[dyslipidemia]] and [[neutropenia]],<ref>{{Cite thesis | vauthors = Højlund M | degree = Ph.D. | publisher = University of Southern Denmark |date=2022-09-12 |title=Low-dose Quetiapine: Utilization and Cardiometabolic Risk |url= https://portal.findresearcher.sdu.dk/en/publications/low-dose-quetiapine-utilization-and-cardiometabolic-risk |language=English |doi=10.21996/mr3m-1783}}</ref><ref>{{cite journal | vauthors = Højlund M, Andersen K, Ernst MT, Correll CU, Hallas J | title = Use of low-dose quetiapine increases the risk of major adverse cardiovascular events: results from a nationwide active comparator-controlled cohort study | journal = World Psychiatry | volume = 21 | issue = 3 | pages = 444–451 | date = October 2022 | pmid = 36073694 | pmc = 9453914 | doi = 10.1002/wps.21010 }}</ref><ref>{{cite journal | vauthors = Pillinger T, McCutcheon RA, Vano L, Mizuno Y, Arumuham A, Hindley G, Beck K, Natesan S, Efthimiou O, Cipriani A, Howes OD | display-authors = 6 | title = Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis | journal = The Lancet. Psychiatry | volume = 7 | issue = 1 | pages = 64–77 | date = January 2020 | pmid = 31860457 | pmc = 7029416 | doi = 10.1016/s2215-0366(19)30416-x }}</ref><ref>{{cite journal | vauthors = Yoshida K, Takeuchi H | title = Dose-dependent effects of antipsychotics on efficacy and adverse effects in schizophrenia | journal = Behavioural Brain Research | volume = 402 | article-number = 113098 | date = March 2021 | pmid = 33417992 | doi = 10.1016/j.bbr.2020.113098 | s2cid = 230507941 | doi-access = free }}</ref> and a recent network meta-analysis of 154 double-blind, randomized controlled trials of drug therapies vs. placebo for insomnia in adults found that quetiapine had not demonstrated any short-term benefits in sleep quality.<ref>{{cite journal | vauthors = De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Kurtulmus A, Tomlinson A, Mitrova Z, Foti F, Del Giovane C, Quested DJ, Cowen PJ, Barbui C, Amato L, Efthimiou O, Cipriani A | display-authors = 6 | title = Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis | language = English | journal = Lancet | volume = 400 | issue = 10347 | pages = 170–184 | date = July 2022 | pmid = 35843245 | doi = 10.1016/S0140-6736(22)00878-9 | s2cid = 250536370 | doi-access = free | hdl = 11380/1288245 | hdl-access = free }}</ref>

===Herbal supplements===
Some [[herb]]al [[dietary supplement|supplement]]s, including [[valerian (herb)|valerian]], [[kava]], [[chamomile]], [[lavender]], [[passion flower]], and [[hops]] among others, are purported to have hypnotic effects and are used to treat sleeping problems, but little to no clinical data are available to support their use.<ref name="Wheatley2005">{{cite journal | vauthors = Wheatley D | title = Medicinal plants for insomnia: a review of their pharmacology, efficacy and tolerability | journal = J Psychopharmacol | volume = 19 | issue = 4 | pages = 414–421 | date = July 2005 | pmid = 15982998 | doi = 10.1177/0269881105053309 | url = }}</ref><ref name="LeachPage2015">{{cite journal | vauthors = Leach MJ, Page AT | title = Herbal medicine for insomnia: A systematic review and meta-analysis | journal = Sleep Med Rev | volume = 24 | issue = | pages = 1–12 | date = December 2015 | pmid = 25644982 | doi = 10.1016/j.smrv.2014.12.003 | url = }}</ref><ref name="VermaSinghSrivastava2022">{{cite journal | vauthors = Verma K, Singh D, Srivastava A | title = The Impact of Complementary and Alternative Medicine on Insomnia: A Systematic Review | journal = Cureus | volume = 14 | issue = 8 | article-number = e28425 | date = August 2022 | pmid = 36176875 | pmc = 9509538 | doi = 10.7759/cureus.28425 | doi-access = free | url = }}</ref><ref name="MeolieRosenKristo2005">{{cite journal | vauthors = Meolie AL, Rosen C, Kristo D, Kohrman M, Gooneratne N, Aguillard RN, Fayle R, Troell R, Townsend D, Claman D, Hoban T, Mahowald M | title = Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence | journal = J Clin Sleep Med | volume = 1 | issue = 2 | pages = 173–187 | date = April 2005 | pmid = 17561634 | doi = 10.5664/jcsm.26314| url = }}</ref><ref name="ValenteMachadoJorge2024">{{cite journal | vauthors = Valente V, Machado D, Jorge S, Drake CL, Marques DR | title = Does valerian work for insomnia? An umbrella review of the evidence | journal = Eur Neuropsychopharmacol | volume = 82 | issue = | pages = 6–28 | date = May 2024 | pmid = 38359657 | doi = 10.1016/j.euroneuro.2024.01.008 | hdl = 10316/115232 | url = }}</ref>

===Other drugs===
Various other types of drugs have also been found to produce hypnotic-type effects in [[scientific research]].<ref name="AtkinComaiGobbi2018" /> Examples include [[histamine]] [[H3 receptor|H<sub>3</sub> receptor]] [[agonist]]s like [[α-methylhistamine]], [[BP 2.94]], [[GT-2203]] (VUF-5296), and [[SCH-50971]],<ref name="Thakkar2011">{{cite journal | vauthors = Thakkar MM | title = Histamine in the regulation of wakefulness | journal = Sleep Med Rev | volume = 15 | issue = 1 | pages = 65–74 | date = February 2011 | pmid = 20851648 | pmc = 3016451 | doi = 10.1016/j.smrv.2010.06.004 | url = }}</ref> [[adenosine]] [[A1 receptor|A<sub>1</sub>]] and [[A2A receptor|A<sub>2A</sub> receptor]] agonists like [[adenosine]] and [[YZG-331]],<ref name="LazarusChenHuang2019">{{cite journal | vauthors = Lazarus M, Chen JF, Huang ZL, Urade Y, Fredholm BB | title = Adenosine and Sleep | journal = Handb Exp Pharmacol | series = Handbook of Experimental Pharmacology | volume = 253 | issue = | pages = 359–381 | date = 2019 | pmid = 28646346 | doi = 10.1007/164_2017_36 | isbn = 978-3-030-11270-7 | url = }}</ref><ref name="AtkinComaiGobbi2018" /><ref name="TangYuYu2022">{{cite journal | vauthors = Tang B, Yu Y, Yu F, Fang J, Wang G, Jiang J, Han Q, Shi J, Zhang J | title = The mechanism study of YZG-331 on sedative and hypnotic effects | journal = Behav Brain Res | volume = 428 | issue = | article-number = 113885 | date = June 2022 | pmid = 35398229 | doi = 10.1016/j.bbr.2022.113885 | url = }}</ref> and [[dopamine]] [[D1 receptor|D<sub>1</sub> receptor]] [[receptor antagonist]]s like [[NNC 01-0687]] (ADX-10061, CEE-03-310, NNC-687).<ref name="MontiMonti2007">{{cite journal | vauthors = Monti JM, Monti D | title = The involvement of dopamine in the modulation of sleep and waking | journal = Sleep Med Rev | volume = 11 | issue = 2 | pages = 113–133 | date = April 2007 | pmid = 17275369 | doi = 10.1016/j.smrv.2006.08.003 | url = }}</ref><ref name="EderZdravkovicWildschiødtz2003">{{cite journal | vauthors = Eder DN, Zdravkovic M, Wildschiødtz G | title = Selective alterations of the first NREM sleep cycle in humans by a dopamine D1 receptor antagonist (NNC-687) | journal = J Psychiatr Res | volume = 37 | issue = 4 | pages = 305–312 | date = 2003 | pmid = 12765853 | doi = 10.1016/s0022-3956(03)00007-4 | url = }}</ref>

===Comparative effectiveness===
A major [[systematic review]] and [[network meta-analysis]] of medications for the treatment of [[insomnia]] was published in 2022.<ref name="DeCrescenzoD'AloOstinelli2022">{{cite journal | vauthors = De Crescenzo F, D'Alò GL, Ostinelli EG, Ciabattini M, Di Franco V, Watanabe N, Kurtulmus A, Tomlinson A, Mitrova Z, Foti F, Del Giovane C, Quested DJ, Cowen PJ, Barbui C, Amato L, Efthimiou O, Cipriani A | display-authors = 6 | title = Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis | journal = Lancet | volume = 400 | issue = 10347 | pages = 170–184 | date = July 2022 | pmid = 35843245 | doi = 10.1016/S0140-6736(22)00878-9 | s2cid = 250536370 | doi-access = free | hdl = 11380/1288245 | hdl-access = free }}</ref> It found a widely varying range of [[effect size]]s ([[standardized mean difference]] or SMD) in terms of [[clinical effectiveness]] for insomnia.<ref name="DeCrescenzoD'AloOstinelli2022" /> The assessed medications and their effect sizes included [[benzodiazepine]]s (e.g., [[temazepam]], [[triazolam]], many others) (SMDs 0.58 to 0.83), [[Z-drug]]s ([[eszopiclone]], [[zaleplon]], [[zolpidem]], [[zopiclone]]) (SMDs 0.03 to 0.63), sedative [[antidepressant]]s and [[antihistamine]]s ([[doxepin]], [[doxylamine]], [[trazodone]], [[trimipramine]]) (SMDs 0.30 to 0.55), the [[antipsychotic]] [[quetiapine]] (SMD 0.07), [[orexin receptor antagonist]]s ([[daridorexant]], [[lemborexant]], [[seltorexant]], [[suvorexant]]) (SMDs 0.23 to 0.44), and [[melatonin receptor agonist]]s ([[melatonin (medication)|melatonin]], [[ramelteon]]) (SMDs 0.00 to 0.13).<ref name="DeCrescenzoD'AloOstinelli2022" /> The [[certainty of evidence]] varied and ranged from high to very low depending on the medication.<ref name="DeCrescenzoD'AloOstinelli2022" /> Certain medications often used as hypnotics, including the antihistamines [[diphenhydramine]], [[hydroxyzine]], and [[promethazine]] and the antidepressants [[amitriptyline]] and [[mirtazapine]] among others, were not included in analyses due to insufficient data.<ref name="DeCrescenzoD'AloOstinelli2022" />

==Risks==
The use of sedative medications in older people generally should be avoided. These medications are associated with poorer health outcomes, including [[cognitive decline]], [[falling (accident)|fall]], and [[bone fracture]]s.<ref>{{Cite journal |last1=Xu |first1=Chong |last2=Leung |first2=Janice Ching Nam |last3=Shi |first3=Jiaying |last4=Lum |first4=Dawn Hei |last5=Lai |first5=Francisco Tsz Tsun |date=February 2024 |title=Sedative-hypnotics and osteoporotic fractures: A systematic review of observational studies with over six million individuals |url=https://linkinghub.elsevier.com/retrieve/pii/S1087079223001223 |journal=Sleep Medicine Reviews |language=en |volume=73 |article-number=101866 |doi=10.1016/j.smrv.2023.101866|pmid=37926010 |url-access=subscription }}</ref> Sedatives and hypnotics should also be avoided in people with [[dementia]], according to the clinical guidelines known as the [[Medication appropriateness tool for co‐morbid health conditions in dementia (MATCH-D) criteria|Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D)]].<ref>Citation error. See the inline comment on how to fix it. {{verify source |date=September 2019 |reason=This ref was deleted Special:Diff/899881486 by a bug in VisualEditor and later identified by a bot. The original cite can be found around Special:Permalink/899881257 (or in a rev close to it) in either cite #24 or cite #23 - find and verify the cite and replace this template with it (1). [[User:GreenC bot/Job 18]]}}</ref> The use of these medications can further impede cognitive function for people with dementia, who are also more sensitive to side effects of medications.{{Citation needed|date=March 2025}} Some hypnotics, such as low-dose [[doxepin]], [[melatonin receptor agonist]]s, and [[orexin receptor antagonist]]s, may be safer and more appropriate in older adults however.<ref name="Leon-BarrieraChaplinKaur2025">{{cite journal | vauthors = León-Barriera R, Chaplin MM, Kaur J, Modesto-Lowe V | title = Insomnia in older adults: A review of treatment options | journal = Cleve Clin J Med | volume = 92 | issue = 1 | pages = 43–50 | date = January 2025 | pmid = 39746731 | doi = 10.3949/ccjm.92a.24073 | url = }}</ref>

==History==
[[File:A corrupt old man tries to seduce a woman by urging Wellcome L0034228.jpg|thumb|''Le Vieux [[seducer|Séducteur]]'' by {{Interlanguage link multi|Charles Motte|fr}}.<br />(A corrupt old man tries to seduce a woman by urging her to take a hypnotic draught in her drink)]]

'''Hypnotica''' was a class of somniferous drugs and substances tested in medicine of the 1890s and later. These include [[Ethyl carbamate|urethan]], [[1,1-Diethoxyethane|acetal]], [[methylal]], [[sulfonal]], [[paraldehyde]], [[tert-Amyl alcohol|amylenhydrate]], [[Acetophenone|hypnon]], chloralurethan, ohloralamid, or chloralimid.<ref>Pacific Record of Medicine and Surgery - Volume 5 - Page 36 1890</ref>

Research about using medications to treat insomnia evolved throughout the last half of the 20th century. Treatment for insomnia in psychiatry dates back to 1869, when [[chloral hydrate]] was first used as a soporific.<ref name="isbn0-19-517668-5">{{cite book |title=A Historical Dictionary of Psychiatry |vauthors=Shorter E |publisher=Oxford University Press |year=2005 |isbn=978-0-19-517668-1 |pages=41–2 |chapter=Benzodiazepines |access-date=2014-02-06 |chapter-url=https://books.google.com/books?id=M49pEDoEpl0C&pg=PA41}}</ref> [[Barbiturate]]s emerged as the first class of drugs in the early 1900s,<ref name="rzepa">{{cite web |title=Barbiturates |url=http://www.ch.ic.ac.uk/rzepa/mim/drugs/html/barbiturate_text.htm |archive-url=https://web.archive.org/web/20071107090620/http://www.ch.ic.ac.uk/rzepa/mim/drugs/html/barbiturate_text.htm |archive-date=2007-11-07 |access-date=2007-10-31}}</ref> after which chemical substitution allowed derivative compounds. Although they were the best drug family at the time (with less toxicity and fewer side effects), they were dangerous in [[drug overdose|overdose]] and tended to cause physical and psychological dependence.<ref>{{cite journal |vauthors=Whitlock FA |date=June 1975 |title=Suicide in Brisbane, 1956 to 1973: the drug-death epidemic |journal=The Medical Journal of Australia |volume=1 |issue=24 |pages=737–743 |doi=10.5694/j.1326-5377.1975.tb111781.x |pmid=239307 |s2cid=28983030}}</ref><ref>{{cite journal |vauthors=Johns MW |year=1975 |title=Sleep and hypnotic drugs |journal=Drugs |volume=9 |issue=6 |pages=448–478 |doi=10.2165/00003495-197509060-00004 |pmid=238826 |s2cid=38775294}}</ref><ref>{{cite journal |vauthors=Jufe GS |date=July–August 2007 |title=[New hypnotics: perspectives from sleep physiology] |journal=Vertex |volume=18 |issue=74 |pages=294–299 |pmid=18265473}}</ref>

During the 1970s, [[quinazolinone]]s<ref>{{Cite journal |vauthors=Voegtle MM, Marzinzik AL |date=July 2004 |title=Synthetic Approaches Towards Quinazolines, Quinazolinones and Quinazolinediones on Solid Phase |journal=QSAR & Combinatorial Science |volume=23 |issue=6 |pages=440–459 |doi=10.1002/qsar.200420018 |issn=1611-020X}}</ref> and [[benzodiazepine]]s were introduced as safer alternatives to replace barbiturates; by the late 1970s, benzodiazepines emerged as the safer drug.<ref name="isbn0-19-517668-5" />

Benzodiazepines are not without their drawbacks; [[substance dependence]] is possible, and deaths from overdoses sometimes occur, especially in combination with [[alcohol (drug)|alcohol]] or other [[depressant]]s. Questions have been raised as to whether they disturb sleep architecture.<ref name="pmid15783240">{{cite journal |vauthors=Barbera J, Shapiro C |year=2005 |title=Benefit-risk assessment of zaleplon in the treatment of insomnia |journal=Drug Safety |volume=28 |issue=4 |pages=301–318 |doi=10.2165/00002018-200528040-00003 |pmid=15783240 |s2cid=24222535}}</ref>

[[Nonbenzodiazepine]]s or Z-drugs like [[zolpidem]] were introduced in the 1990s and 2000s. Although it is clear that they are less toxic than barbiturates, their predecessors, comparative efficacy over benzodiazepines has not been established. Such efficacy is hard to determine without [[longitudinal studies]]. However, some psychiatrists recommend these drugs, citing research suggesting they are equally potent with less potential for abuse.<ref name="pmid9640488a" />

[[Orexin receptor antagonist]]s like [[suvorexant]] were introduced in the 2010s and 2020s.<ref name="MuehlanRochVaillant2023">{{cite journal | vauthors = Muehlan C, Roch C, Vaillant C, Dingemanse J | title = The orexin story and orexin receptor antagonists for the treatment of insomnia | journal = J Sleep Res | volume = 32 | issue = 6 | article-number = e13902 | date = December 2023 | pmid = 37086045 | doi = 10.1111/jsr.13902 | url = }}</ref>

==See also==
* [[Insomnia#Medications|Insomnia § Medications]]
* [[List of investigational insomnia drugs]]

== Notes ==
<references group="note" />

== References ==
{{Reflist||colwidth=30em}}

== Further reading ==
{{refbegin|30em}}
* {{cite book | chapter-url=http://www.acnp.org/g4/GN401000173/CH169.html | vauthors = Harrison N, Mendelson WB, de Wit H |chapter = Barbiturates | veditors = Bloom FE, Kupfer DJ | title = Psychopharmacology | edition = The Fourth Generation of Progress |year=2000 | location = New York | publisher = Raven Press }} discusses Barbs vs. benzos
* {{cite journal | vauthors = Buysse DJ | title = Insomnia | journal = JAMA | volume = 309 | issue = 7 | pages = 706–716 | date = February 2013 | pmid = 23423416 | pmc = 3632369 | doi = 10.1001/jama.2013.193 }}
* {{cite journal | vauthors = Huedo-Medina TB, Kirsch I, Middlemass J, Klonizakis M, Siriwardena AN | title = Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration | journal = BMJ | volume = 345 | article-number = e8343 | date = December 2012 | pmid = 23248080 | pmc = 3544552 | doi = 10.1136/bmj.e8343 }}
* {{cite journal | vauthors = Roehrs T, Roth T | title = Insomnia pharmacotherapy | journal = Neurotherapeutics | volume = 9 | issue = 4 | pages = 728–738 | date = October 2012 | pmid = 22976558 | pmc = 3480571 | doi = 10.1007/s13311-012-0148-3 }}
* {{cite journal | vauthors = Passos GS, Poyares DL, Santana MG, Tufik S, Mello MT | title = Is exercise an alternative treatment for chronic insomnia? | journal = Clinics | volume = 67 | issue = 6 | pages = 653–660 | date = 2012 | pmid = 22760906 | pmc = 3370319 | doi = 10.6061/clinics/2012(06)17 }}
* {{cite journal | vauthors = Becker DE | title = Pharmacodynamic considerations for moderate and deep sedation | journal = Anesthesia Progress | volume = 59 | issue = 1 | pages = 28–42 | date = Spring 2012 | pmid = 22428972 | pmc = 3309299 | doi = 10.2344/0003-3006-59.1.28 }}
* {{cite journal | vauthors = Godard M, Barrou Z, Verny M | title = [Geriatric approach of sleep disorders in the elderly] | journal = Psychologie & NeuroPsychiatrie du Vieillissement| volume = 8 | issue = 4 | pages = 235–241 | date = December 2010 | pmid = 21147662 | pmc =   | doi = 10.1684/pnv.2010.0232 }}
* {{cite journal | vauthors = Scammell TE, Winrow CJ | title = Orexin receptors: pharmacology and therapeutic opportunities | journal = Annual Review of Pharmacology and Toxicology | volume = 51 | pages = 243–266 | date = 2011 | pmid = 21034217 | pmc = 3058259 | doi = 10.1146/annurev-pharmtox-010510-100528 }}
* {{cite journal | vauthors = Sukys-Claudino L, Moraes WA, Tufik S, Poyares D | title = [The newer sedative-hypnotics] | journal = Revista Brasileira de Psiquiatria | volume = 32 | issue = 3 | pages = 288–293 | date = September 2010 | pmid = 20945020 | doi = 10.1590/S1516-44462010000300014 | doi-access = free }}
* {{cite journal | vauthors = Uzun S, Kozumplik O, Jakovljević M, Sedić B | title = Side effects of treatment with benzodiazepines | journal = Psychiatria Danubina | volume = 22 | issue = 1 | pages = 90–93 | date = March 2010 | pmid = 20305598 | url = http://hrcak.srce.hr/48626 }}
* {{cite journal | vauthors = Pigeon WR | title = Diagnosis, prevalence, pathways, consequences & treatment of insomnia | journal = The Indian Journal of Medical Research | volume = 131 | pages = 321–332 | date = February 2010 | pmid = 20308757 | pmc = 4324320 }}
* {{cite journal | vauthors = Hoque R, Chesson AL | title = Zolpidem-induced sleepwalking, sleep related eating disorder, and sleep-driving: fluorine-18-flourodeoxyglucose positron emission tomography analysis, and a literature review of other unexpected clinical effects of zolpidem | journal = Journal of Clinical Sleep Medicine | volume = 5 | issue = 5 | pages = 471–476 | date = October 2009 | pmid = 19961034 | pmc = 2762721 | doi = 10.5664/jcsm.27605 }}
{{refend}}

== External links ==
{{Wiktionary}}
* [http://www.circadin.com/treatments/sleeping-pills/ Sleeping pills overview]

{{Hypnotics and sedatives}}
{{Insomnia pharmacotherapies}}
{{Major drug groups}}
{{Chemical classes of psychoactive drugs}}
{{Authority control}}

{{DEFAULTSORT:Hypnotic}}

[[Category:Hypnotics| ]]
[[Category:Treatment of sleep disorders]]