Chemistry:Hypnotic

From HandWiki

A hypnotic (from Greek Hypnos, sleep[1]), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to induce sleep[2] 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.[3][4] Certain hypnotics can be used to treat non-restorative sleep and associated symptoms in conditions like fibromyalgia as well.[5][4][6][7]

This group of drugs is related to sedatives. Whereas the term sedative describes drugs that serve to calm or 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.[8]

Hypnotic drugs are regularly prescribed for insomnia and other sleep disorders, with over 95% of insomnia patients being prescribed hypnotics in some countries.[9] 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 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.[10]

Among individuals with sleep disorders, 13.7% are taking or prescribed nonbenzodiazepines (Z-drugs), while 10.8% are taking benzodiazepines, as of 2010, in the USA.[11] Early classes of drugs, such as barbiturates, 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 terrors or sleepwalking.[12] 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.[13] A review of the literature regarding benzodiazepine hypnotics and Z-drugs concluded that these drugs have adverse effects, such as 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.[14]

Falling outside the above-mentioned categories, the neurohormone melatonin and its analogues (e.g., ramelteon) serve a hypnotic function.[15]

Types

GABAA receptor positive allosteric modulators

Main article: Chemistry:GABAA receptor positive allosteric modulator

Benzodiazepines

Benzodiazepines 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.[16][17] Like 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).[18][19][20]

Other drawbacks of hypnotics, including benzodiazepines, are possible 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.[21][22] 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.[17] Longer-acting benzodiazepines, such as nitrazepam and diazepam, have residual effects that may persist into the next day and are, in general, not recommended.[16]

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.[16][22] 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.[22] Some experts suggest using nonbenzodiazepines preferentially as a first-line long-term treatment of insomnia.[17] 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.[16]

Older adults should not use benzodiazepines to treat insomnia unless other treatments have failed to be effective.[23] 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.[9][23]

Their mechanism of action is primarily at GABAA receptors.[24]

Nonbenzodiazepines

Main article: Biology:Nonbenzodiazepine

Nonbenzodiazepines (Z-drugs) are a class of psychoactive drugs 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.[25][26]

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.[27]

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),[note 1] as next-day impairments were minimal.[28] 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 tolerance to nonbenzodiazepines may be slower to develop than with benzodiazepines. A different team was more skeptical, finding little benefit over benzodiazepines.[29]

Barbiturates

Main article: Chemistry:Barbiturate

Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a broad spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, 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 and psychological. Barbiturates have now largely been replaced by benzodiazepines in routine medical practice – such as in the treatment of anxiety and insomnia – mainly because benzodiazepines are significantly less dangerous in 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 modulation of GABAA receptors.[30] Barbiturates are derivatives of barbituric acid. Examples include amobarbital, pentobarbital, phenobarbital, secobarbital, and sodium thiopental.

Quinazolinones

Main articles: Chemistry:Quinazolinone and Methaqualone

Quinazolinones 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 article: Biology:Neurosteroid

Oral progesterone (Prometrium) metabolizes into neurosteroids including allopregnanolone and pregnanolone which act as potent GABAA receptor positive allosteric modulators.[31][32][33] As a result, oral progesterone can dose-dependently produce side effects including dizziness, drowsiness, sedation, somnolence, fatigue, anxiety reduction, euphoria, and cognitive impairment.[34][35][36] For this reason, oral progesterone is often taken at night before bed.[37] Oral progesterone taken before bed has been found to improve multiple sleep outcomes in clinical studies.[38][39] Zuranolone is a synthetic analogue of allopregnanolone that likewise acts as a GABAA receptor positive allosteric modulator but is orally active.[40] It is under development for the treatment of insomnia and is in phase 3 clinical trials for this indication as of September 2025.[41][42]

Others

Other GABAA receptor positive allosteric modulators with hypnotic effects include alcohol (ethanol), chloral hydrate, urethane (ethyl carbamate), isoflurane, allopregnanolone (brexanolone), and propofol, among others.[43][44]

GABAA receptor agonists

The GABAA receptor agonist gaboxadol (THIP; LU-2-030), a synthetic derivative of the neurotransmitter γ-aminobutyric acid (GABA) and an analogue of the alkaloid muscimol, underwent formal clinical development for the treatment of insomnia and reached phase 3 clinical trials for this indication in the 1990s and 2000s.[45][46][47] It was found to effectively improve sleep onset and duration in people with insomnia.[45] In addition, and unlike other hypnotics like benzodiazepines, gaboxadol improved slow wave sleep, preserved sleep architecture, and did not suppress REM sleep.[45] Moreover, in contrast to benzodiazepines, tolerance did not appear to develop to gaboxadol's hypnotic effects.[45]

The development of gaboxadol was discontinued in 2007.[47][48][49] This was due to high rates of psychiatric and hallucinogenic effects in drug users at supratherapeutic doses, failure of a 3-month efficacy trial, and other cited reasons.[47][48][50] 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.[47] 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.[47] There has been some further study of gaboxadol as a hypnotic by David Nutt and colleagues following the discontinuation of its development.[51][52]

Muscimol, the compound from which gaboxadol was derived, is a naturally occurring constituent of Amanita mushrooms such as Amanita muscaria (fly agaric) and is a potent GABAA receptor agonist similarly.[53][54] However, muscimol is less selective, more toxic, and far less-researched than gaboxadol.[53][55][54][56] Muscimol is reported to induce sleep in humans in addition to its well-known hallucinogenic effects that occur at sufficiently high doses.[53][57] The drug shows similar effects on sleep in rodents as gaboxadol.[58][54][45] 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.[53][59][60]

GABAB receptor agonists

The GABAB receptor agonist sodium oxybate (SXB; Xyrem), also known as γ-hydroxybutyrate (GHB), has hypnotic and sleep-improving effects.[3][61][5] 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.[3][61][5][62] The drug is approved and clinically used in the treatment of narcolepsy and excessive daytime sleepiness (EDS).[3][4] 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.[3][62] The robust enhancement of slow wave sleep by sodium oxybate is unusual and potentially advantageous relative to other hypnotics.[63][6][64] In addition, unlike the case of many other hypnotics, tolerance does not appear to develop to the hypnotic effects of sodium oxybate.[65][4]

Sodium oxybate also completed formal clinical development for fibromyalgia.[5][66] This condition has very high rates of non-restorative sleep (unrefreshing sleep) that may be directly involved in its symptoms.[67][68][6][69] Sodium oxybate improved sleep in fibromyalgia and showed moderate effectiveness in treating multiple symptoms across the condition including pain and fatigue.[5] However, despite its effectiveness, sodium oxybate was ultimately not approved for treatment of fibromyalgia owing mostly to concerns about possible misuse.[5] 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.[4][69][67][70] In addition, sodium oxybate was limitedly studied to improve insomnia in people with depression or bipolar disorder.[4] However, it was reported to paradoxically disrupt sleep and induce narcolepsy-like changes in these individuals.[4] Moreover, concerns about misuse have limited use of sodium oxybate for other medical conditions.[71] GHB has also garnered a reputation as a date-rape drug, although the actual prevalence of this appears to be much lower than popular perception.[72]

The GABAB 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.[69][73][74] However, in people with narcolepsy, baclofen and sodium oxybate both improved sleep but only sodium oxybate reduced daytime sleepiness.[74] In any case, research in this area is limited, and there remains significant interest in baclofen in the potential treatment of sleeping problems.[73][69] Unlike sodium oxybate, baclofen is not a controlled substance and has much less or no misuse potential.[74][75] Baclofen and sodium oxybate have been found to activate the GABAB receptor differently, which is thought to underlie the differences in their effects.[74] 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 hours versus 0.5–1.0 hours, respectively).[73][76][75]

GABA reuptake inhibitors

The GABA transporter 1 (GAT-1) and GABA reuptake inhibitor tiagabine (Gabitril) is approved and clinically used as an anticonvulsant.[77] It has also been used off-label in the treatment of anxiety disorders and other conditions.[78] 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).[77][64] In addition, tiagabine has been reported to make sleep feel more restorative and to improve some cognitive outcomes.[77][64] The drug has an elimination half-life of 5 to 8 hours.[79] While tiagabine may have hypnotic effects, off-label use is discouraged as it has been associated with new-onset seizures in people without epilepsy.[80][81][82]

Melatonin receptor agonists

Main article: Chemistry:Melatonin receptor agonist

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 diurnal mammals.[83] It activates the melatonin MT1 and MT2 receptors to produce beneficial effects on sleep, therefore being used exogenously for mild insomnia.[84] A small improvement in sleep onset and total sleep time by using melatonin has been shown in recent systematic reviews.[85] Synthetic analogues of melatonin, or melatonin receptor agonists, 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.[86]

Histamine H1 receptor antagonists

Main article: Chemistry:H1 antagonist

Antihistamines, also known as histamine H1 receptor antagonists, are a class of drugs that inhibit action at histamine H1 receptors. They are clinically used to alleviate allergic reactions including allergic rhinitis, allergic conjunctivitis, and urticaria, which are mediated by histamine. First-generation antihistamines, 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.[87] Many sedating antihistamines also have anticholinergic activity that can produce side effects like cognitive impairment.[88][89] Low-dose doxepin (Silenor) is approved by the FDA for the treatment of insomnia.[90] Non-selective hypnotics that possess histamine H1 receptor antagonism include the antidepressants amitriptyline, high-dose doxepin, trazodone, and trimipramine; the antipsychotics olanzapine and quetiapine; and the antihistamines hydroxyzine, promethazine, and cyproheptadine, among others.[88][91][92][93] Second-generation antihistamines such as cetirizine and loratadine produce much less if any sedation due to a greatly reduced capacity to cross the blood–brain barrier.[94]

Orexin receptor antagonists

Orexin receptor antagonists are drugs that block the orexin OX1 and/or OX2 receptors, hence reducing the wakefulness-promoting effects of the orexin system and inducing sleep.[95] Non-selective orexin receptor antagonists including suvorexant, lemborexant, and daridorexant and selective orexin OX2 receptor antagonists like seltorexant have been shown in clinical studies to improve sleep onset, sleep duration, and sleep quality.[96][97][98]

Serotonin 5-HT2A receptor antagonists

Serotonin 5-HT2A receptor antagonists such as ritanserin, ketanserin, eplivanserin, volinanserin, nelotanserin, and pimavanserin have been studied and developed to improve sleep.[99][100] They do not improve sleep onset, but have been found to increase slow wave sleep (deep sleep) and reduce nighttime awakenings.[99][100] Conversely, improvement in subjective sleep ratings have been more mixed.[99] Ultimately no selective serotonin 5-HT2A receptor antagonists have been approved for treatment of insomnia.[99] The only selective serotonin 5-HT2A receptor antagonist to be approved for any indication is pimavanserin for treatment of Parkinson's disease psychosis.[100] Besides selective serotonin 5-HT2A receptor antagonists however, many non-selective agents used as hypnotics show serotonin 5-HT2A receptor antagonism, for instance antidepressants like trazodone, mirtazapine, and amitriptyline, antipsychotics like quetiapine and olanzapine, and antihistamines like hydroxyzine and cyproheptadine.[101][102][103][91][89]

Gabapentinoids

Main article: Chemistry:Gabapentinoid

Gabapentinoids, also known as α2δ subunit-containing voltage-gated calcium channel ligands, include drugs like gabapentin, pregabalin, and gabapentin enacarbil.[104] They have been found to increase slow wave sleep (deep sleep) in people with insomnia and healthy individuals.[105][102] However, they do not appear to improve sleep onset.[105] The gabapentinoid atagabalin (PD-0200390) was under formal development for treatment of insomnia, but development was discontinued following unsatisfactory clinical trial results.[105] 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.[106][107]

Cannabinoids

Main articles: Chemistry:Cannabinoid and Cannabis (drug)

Cannabinoids, or cannabinoid receptor agonists, such as the δ9-tetrahydrocannabinol (THC) found in cannabis, have been found to be effective in improving sleep in healthy people and in people with insomnia.[108][109] They have been found to improve sleep onset, sleep duration, and sleep quality.[108][109] Cannabidiol (CBD), which acts differently than other cannabinoids like THC, is not effective in improving sleep on the other hand.[108] Zenivol is a cannabis extract which is approved for the treatment of insomnia in Germany.[110][109]

α1- and β-adrenergic receptor antagonists

Main articles: Chemistry:Alpha-1 blocker and Beta blocker

The α1-adrenergic receptor antagonist prazosin is used off-label to treat insomnia, nightmares, and poor sleep quality in people with post-traumatic stress disorder (PTSD).[111][112][113][114] It is clinically effective for this purpose.[112][113][114] However, the drug is also an antihypertensive agent and can lower blood pressure, thereby producing side effects like dizziness and orthostatic hypotension.[111] Certain non-selective hypnotics such as trazodone and tricyclic antidepressants (TCAs) like amitriptyline and trimipramine are also α1-adrenergic receptor antagonists.[105][115][116] The combination of prazosin and the centrally-penetrant beta blocker (β-adrenergic receptor antagonist) timolol has been found to be synergistic in producing sedative and hypnotic effects in animals.[105][117] Conversely, timolol alone produced no such effects.[105][117] 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.[118][119][120] Certain beta blockers like labetalol and carvedilol also block the α1-adrenergic receptor to varying extents and have been associated with somnolence as a side effect.[91][121][122] However, these two beta blockers have also been associated with insomnia similarly to selective beta blockers.[91]

α2-Adrenergic receptor agonists

α2-Adrenergic receptor agonists like clonidine can improve sleep and may be useful in the treatment of insomnia.[105][123][124] An example of this is in the treatment of insomnia in children and adolescents with attention deficit hyperactivity disorder (ADHD), for instance due stimulant therapy.[123][124][125] Similarly to clonidine, the α2-adrenergic receptor agonist dexmedetomidine has sedative and hypnotic effects and is used to produce sedation in hospital settings.[126] The sleep induced by dexmedetomidine is said to closely resemble natural sleep.[126][127][128] The selective α2A-adrenergic receptor agonist tasipimidine (ODM-105) is under development for the treatment of insomnia and is in phase 2 clinical trials for this indication as of October 2024.[129][130] α2-Adrenergic receptor agonists can produce hypotension and bradycardia as side effects, which has limited their use.[131][126] Activation of the α2A-adrenergic receptor is thought to be responsible for most of the physiological effects of the α2-adrenergic receptors, including hypotension.[129] On the other hand, the preferential α2A-adrenergic receptor agonist guanfacine appears to show less sedation and hypotension than clonidine.[132]

Serotonin precursors

The serotonin precursors tryptophan and 5-hydroxytryptophan (5-HTP; oxitriptan) are available as over-the-counter supplements.[133][134] They are often used to produce sleepiness and treat insomnia.[133][134] However, little to no clinical data exist to support their use or effectiveness.[133]

Multiple mechanisms

Antidepressants

Some antidepressants have hypnotic and/or sedative effects.[105] These include the serotonin antagonist and reuptake inhibitor (SARI) trazodone,[135] tricyclic antidepressants (TCAs) such as amitriptyline,[136] doxepin,[137] and trimipramine,[138] and tetracyclic antidepressants (TeCAs) like mirtazapine[139][140] and mianserin.[141][105] These agents produce their hypnotic and sedative effects via multiple mechanisms of action that may include histamine H1 receptor antagonism, serotonin 5-HT2A receptor antagonism, and α1-adrenergic receptor antagonism.[105] Some hypnotic antidepressants, such as trazodone and mirtazapine, have been shown to enhance slow wave sleep, which may be due to serotonin 5-HT2A receptor antagonism.[77]

Antipsychotics

Certain typical antipsychotics (first-generation) like chlorpromazine and atypical antipsychotics (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.[142][143] However, the most commonly used agents for insomnia are quetiapine and olanzapine.[105][144] They are thought to produce these effects via multiple mechanisms of action, including histamine H1 receptor antagonism, serotonin 5-HT2A receptor antagonism, α1-adrenergic receptor antagonism, and/or dopamine D2 receptor antagonism.[105][142] 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 antipsychotics as the risks frequently outweigh the benefits.[145][146] 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,[147][148][149][150] 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.[151]

Herbal supplements

Some herbal supplements, including 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.[152][153][154][133][155]

Other drugs

Various other types of drugs have also been found to produce hypnotic-type effects in scientific research.[105] Examples include histamine H3 receptor agonists like α-methylhistamine, BP 2.94, GT-2203 (VUF-5296), and SCH-50971,[156] adenosine A1 and A2A receptor agonists like adenosine and YZG-331,[157][105][158] and dopamine D1 receptor receptor antagonists like NNC 01-0687 (ADX-10061, CEE-03-310, NNC-687).[159][160]

Comparative effectiveness

A major systematic review and network meta-analysis of medications for the treatment of insomnia was published in 2022.[97] It found a widely varying range of effect sizes (standardized mean difference or SMD) in terms of clinical effectiveness for insomnia.[97] The assessed medications and their effect sizes included benzodiazepines (e.g., temazepam, triazolam, many others) (SMDs 0.58 to 0.83), Z-drugs (eszopiclone, zaleplon, zolpidem, zopiclone) (SMDs 0.03 to 0.63), sedative antidepressants and antihistamines (doxepin, doxylamine, trazodone, trimipramine) (SMDs 0.30 to 0.55), the antipsychotic quetiapine (SMD 0.07), orexin receptor antagonists (daridorexant, lemborexant, seltorexant, suvorexant) (SMDs 0.23 to 0.44), and melatonin receptor agonists (melatonin, ramelteon) (SMDs 0.00 to 0.13).[97] The certainty of evidence varied and ranged from high to very low depending on the medication.[97] 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.[97]

Risks

The use of sedative medications in older people generally should be avoided. These medications are associated with poorer health outcomes, including cognitive decline, fall, and bone fractures.[161] Sedatives and hypnotics should also be avoided in people with dementia, according to the clinical guidelines known as the Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D).[162] The use of these medications can further impede cognitive function for people with dementia, who are also more sensitive to side effects of medications. Some hypnotics, such as low-dose doxepin, melatonin receptor agonists, and orexin receptor antagonists, may be safer and more appropriate in older adults however.[163]

History

Le Vieux Séducteur by Charles Motte [fr; fr].
(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 urethan, acetal, methylal, sulfonal, paraldehyde, amylenhydrate, hypnon, chloralurethan, ohloralamid, or chloralimid.[164]

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.[165] Barbiturates emerged as the first class of drugs in the early 1900s,[166] 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 overdose and tended to cause physical and psychological dependence.[167][168][169]

During the 1970s, quinazolinones[170] and benzodiazepines were introduced as safer alternatives to replace barbiturates; by the late 1970s, benzodiazepines emerged as the safer drug.[165]

Benzodiazepines are not without their drawbacks; substance dependence is possible, and deaths from overdoses sometimes occur, especially in combination with alcohol or other depressants. Questions have been raised as to whether they disturb sleep architecture.[171]

Nonbenzodiazepines 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.[25]

Orexin receptor antagonists like suvorexant were introduced in the 2010s and 2020s.[172]

See also

Notes

  1. ↑ 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.

References

  1. ↑ "Definition of HYPNOTIC" (in en). https://www.merriam-webster.com/dictionary/hypnotic. 
  2. ↑ "Dorlands Medical Dictionary:hypnotic". http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.jsp?pg=/ppdocs/us/common/dorlands/dorland/four/000051451.htm. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "The use of sodium oxybate to treat narcolepsy". Expert Rev Neurother 12 (5): 519–529. May 2012. doi:10.1586/ern.12.42. PMID 22550980. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Broughton, Roger (2015). "Gamma-Hydroxybutyrate (Sodium Oxybate): From the Initial Synthesis to the Treatment of Narcolepsy–Cataplexy and Beyond". Sleep Medicine. New York, NY: Springer New York. pp. 557–571. doi:10.1007/978-1-4939-2089-1_63. ISBN 978-1-4939-2088-4. https://link.springer.com/10.1007/978-1-4939-2089-1_63. Retrieved 29 September 2025. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "Sodium oxybate for the treatment of fibromyalgia". Expert Opin Pharmacother 12 (11): 1789–1798. August 2011. doi:10.1517/14656566.2011.589836. PMID 21679091. 
  6. ↑ 6.0 6.1 6.2 "The significance, assessment, and management of nonrestorative sleep in fibromyalgia syndrome". CNS Spectr 13 (3 Suppl 5): 22–26. March 2008. doi:10.1017/s1092852900026808. PMID 18323770. 
  7. ↑ Moldofsky, Harvey (2015). "Nonrestorative Sleep, Musculoskeletal Pain, Fatigue in Rheumatic Disorders, and Allied Syndromes: A Historical Perspective". Sleep Medicine. New York, NY: Springer New York. pp. 423–431. doi:10.1007/978-1-4939-2089-1_48. ISBN 978-1-4939-2088-4. 
  8. ↑ "17: Hypnotics and Sedatives". Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). The McGraw-Hill Companies, Inc.. 2006. ISBN 978-0-07-146804-6. http://accessmedicine.mhmedical.com/content.aspx?bookid=374&sectionid=41266223. Retrieved 2014-02-06. 
  9. ↑ 9.0 9.1 National Prescribing Service (2 February 2010). "NPS News 67: Addressing hypnotic medicines use in primary care". http://www.nps.org.au/health_professionals/publications/nps_news/current/nps_news_67. 
  10. ↑ "Criteria for selection of appropriate benzodiazepine hypnotic therapy". The Journal of Clinical Psychiatry. 52 52 (Suppl): 42–46. September 1991. PMID 1680126. 
  11. ↑ "Trends in prescribing of sedative-hypnotic medications in the USA: 1993-2010". Pharmacoepidemiology and Drug Safety 25 (6): 637–645. June 2016. doi:10.1002/pds.3951. PMID 26711081. 
  12. ↑ Psychiatry (3rd ed.). New York: Oxford. 2005. p. 238. 
  13. ↑ "Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits". BMJ 331 (7526): 1169. November 2005. doi:10.1136/bmj.38623.768588.47. PMID 16284208. 
  14. ↑ "What's wrong with prescribing hypnotics?". Drug and Therapeutics Bulletin 42 (12): 89–93. December 2004. doi:10.1136/dtb.2004.421289. PMID 15587763. 
  15. ↑ "Melatonin as a hypnotic: pro". Sleep Medicine Reviews 9 (1): 51–65. February 2005. doi:10.1016/j.smrv.2004.04.003. PMID 15649738. 
  16. ↑ 16.0 16.1 16.2 16.3 "Technology Appraisal Guidance 77. Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia". National Institute for Clinical Excellence. April 2004. http://www.nice.org.uk/nicemedia/pdf/TA077fullguidance.pdf. 
  17. ↑ 17.0 17.1 17.2 "Treatment options for insomnia". American Family Physician 76 (4): 517–526. August 2007. PMID 17853625. http://www.aafp.org/afp/2007/0815/p517.html. 
  18. ↑ "The diagnosis and management of benzodiazepine dependence". Current Opinion in Psychiatry 18 (3): 249–255. May 2005. doi:10.1097/01.yco.0000165594.60434.84. PMID 16639148. 
  19. ↑ "Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse". Behaviour Research and Therapy 43 (1): 1–14. January 2005. doi:10.1016/j.brat.2003.12.002. PMID 15531349. 
  20. ↑ "Chronic benzodiazepine usage and withdrawal in insomnia patients". Journal of Psychiatric Research 38 (3): 327–334. 2004-06-01. doi:10.1016/j.jpsychires.2003.10.003. PMID 15003439. 
  21. ↑ Handbook of Integrative Clinical Psychology, Psychiatry, and Behavioral Medicine: Perspectives, Practices, and Research. Springer Publishing Company. 13 December 2009. pp. 128–30. ISBN 978-0-8261-1094-7. https://books.google.com/books?id=4Tkdm1vRFbUC. 
  22. ↑ 22.0 22.1 22.2 "Manifestations and management of chronic insomnia in adults". Evidence Report/Technology Assessment (Agency for Healthcare Research and Quality) (125): 1–10. June 2005. doi:10.1037/e439752005-001. PMID 15989374. 
  23. ↑ 23.0 23.1 "Five Things Physicians and Patients Should Question". Choosing Wisely: an initiative of the ABIM Foundation. American Geriatrics Society. http://www.choosingwisely.org/doctor-patient-lists/american-geriatrics-society/. , which cites
  24. ↑ "GABA and glycine". Basic Neurochemistry: Molecular, Cellular and Medical Aspects (7th ed.). Elsevier. 2006. pp. 291–302. ISBN 978-0-12-088397-4. 
  25. ↑ 25.0 25.1 "Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia". The Annals of Pharmacotherapy 32 (6): 680–691. June 1998. doi:10.1345/aph.17111. PMID 9640488. 
  26. ↑ "GPs' attitudes to benzodiazepine and 'Z-drug' prescribing: a barrier to implementation of evidence and guidance on hypnotics". The British Journal of General Practice 56 (533): 964–967. December 2006. PMID 17132386. 
  27. ↑ Ryba, Nicole; Rainess, Rebecca (2020). "Z-drugs and Falls: A Focused Review of the Literature". The Senior Care Pharmacist 35 (12): 549–554. doi:10.4140/tcp.n.2020.549. PMID 33258763. 
  28. ↑ "Diagnosis and treatment of chronic insomnia: a review". Psychiatric Services 56 (3): 332–343. March 2005. doi:10.1176/appi.ps.56.3.332. PMID 15746509. "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.". 
  29. ↑ "Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia". The Annals of Pharmacotherapy 32 (6): 680–691. June 1998. doi:10.1345/aph.17111. PMID 9640488. "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.". 
  30. ↑ "How theories evolved concerning the mechanism of action of barbiturates". Epilepsia 53 (Suppl 8): 12–25. December 2012. doi:10.1111/epi.12025. PMID 23205959. 
  31. ↑ "Progesterone: review of safety for clinical studies". Exp Clin Psychopharmacol 15 (5): 427–444. 2007. doi:10.1037/1064-1297.15.5.427. PMID 17924777. https://www.researchgate.net/publication/5919868. 
  32. ↑ "The pharmacodynamics and safety of progesterone". Best Pract Res Clin Obstet Gynaecol 69: 13–29. November 2020. doi:10.1016/j.bpobgyn.2020.06.002. PMID 32739288. 
  33. ↑ "Positive GABAA receptor modulating steroids and their antagonists: Implications for clinical treatments". J Neuroendocrinol 34 (2). February 2022. doi:10.1111/jne.13013. PMID 34337790. 
  34. ↑ Menopause. ACP Press. 2007. p. 97. ISBN 978-1-930513-83-9. https://books.google.com/books?id=mPs5Ly71OCQC&pg=PA97. 
  35. ↑ Estrogen Effects in Psychiatric Disorders. Springer Science & Business Media. 27 December 2005. p. 179. ISBN 978-3-211-27063-9. https://books.google.com/books?id=L4YQ50SbBnsC&pg=PA179. 
  36. ↑ "Allopregnanolone and mood disorders". Prog. Neurobiol. 113: 88–94. 2014. doi:10.1016/j.pneurobio.2013.07.005. PMID 23978486. 
  37. ↑ "The case for progesterone". Ann N Y Acad Sci 1052 (1): 152–169. June 2005. doi:10.1196/annals.1347.011. PMID 16024758. Bibcode: 2005NYASA1052..152S. 
  38. ↑ "Efficacy of Micronized Progesterone for Sleep: A Systematic Review and Meta-analysis of Randomized Controlled Trial Data". J Clin Endocrinol Metab 106 (4): 942–951. March 2021. doi:10.1210/clinem/dgaa873. PMID 33245776. 
  39. ↑ "Evidence on the use of progesterone in menopausal hormone therapy". Climacteric 21 (4): 346–354. August 2018. doi:10.1080/13697137.2018.1455657. PMID 29630427. 
  40. ↑ "Zuranolone - synthetic neurosteroid in treatment of mental disorders: narrative review". Front Psychiatry 14. 2023. doi:10.3389/fpsyt.2023.1298359. PMID 38116383. 
  41. ↑ "Emerging and upcoming therapies in insomnia". Transl Clin Pharmacol 32 (1): 1–17. March 2024. doi:10.12793/tcp.2024.32.e5. PMID 38586124. 
  42. ↑ "Biogen/SAGE Therapeutics". 22 September 2025. https://adisinsight.springer.com/drugs/800043382. 
  43. ↑ "Sleep circuitry and the hypnotic mechanism of GABAA drugs". J Clin Sleep Med 2 (2): S19–S26. April 2006. doi:10.5664/jcsm.26527. PMID 17557503. 
  44. ↑ Pleuvry, Barbara J (2004). "Anxiolytics and hypnotics". Anaesthesia & Intensive Care Medicine 5 (8): 252–256. doi:10.1383/anes.5.8.252.43294. https://linkinghub.elsevier.com/retrieve/pii/S1472029906003511. Retrieved 2 October 2025. 
  45. ↑ 45.0 45.1 45.2 45.3 45.4 "Gaboxadol--a new awakening in sleep". Curr Opin Pharmacol 6 (1): 30–36. February 2006. doi:10.1016/j.coph.2005.10.004. PMID 16368265. 
  46. ↑ Sorbera, L.A.; Castaner, J.; Silvestre, J.S. (2004). "Gaboxadol". Drugs of the Future 29 (5): 0449. doi:10.1358/dof.2004.029.05.803754. http://access.portico.org/stable?au=pjbf78x8shw. Retrieved 30 September 2025. 
  47. ↑ 47.0 47.1 47.2 47.3 47.4 Morris, Hamilton (2013). "Gaboxadol, by Hamilton Morris". https://harpers.org/archive/2013/08/gaboxadol/. 
  48. ↑ 48.0 48.1 "Merck, Lundbeck scrap insomnia drug after trials". 9 August 2007. https://www.reuters.com/article/business/merck-lundbeck-scrap-insomnia-drug-after-trials-idUSN28285490/. 
  49. ↑ "Merck & Co and Lundbeck's sleep drug terminated in Phase III". 29 March 2007. https://pharmatimes.com/news/merck_and_co_and_lundbecks_sleep_drug_terminated_in_phase_iii_989624/. "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." 
  50. ↑ "Discontinuation of development program for gaboxadol in insomnia". https://www.lundbeck.com/investor/Presentations/Teleconference/Teleconference_gaboxadol_20070328.pdf. 
  51. ↑ "Drug development in psychiatry: 50 years of failure and how to resuscitate it". Lancet Psychiatry 12 (3): 228–238. March 2025. doi:10.1016/S2215-0366(24)00370-5. PMID 39952266. 
  52. ↑ "Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: a study in healthy volunteers". Neuropharmacology 88: 155–163. January 2015. doi:10.1016/j.neuropharm.2014.08.017. PMID 25195191. 
  53. ↑ 53.0 53.1 53.2 53.3 "Classics in Chemical Neuroscience: Muscimol". ACS Chem Neurosci 15 (18): 3257–3269. September 2024. doi:10.1021/acschemneuro.4c00304. PMID 39254100. 
  54. ↑ 54.0 54.1 54.2 "Muscimol as an ionotropic GABA receptor agonist". Neurochem Res 39 (10): 1942–1947. October 2014. doi:10.1007/s11064-014-1245-y. PMID 24473816. https://core.ac.uk/download/pdf/357370693.pdf. "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].". 
  55. ↑ "GABA(A) receptor ligands and their therapeutic potentials". Curr Top Med Chem 2 (8): 817–832. August 2002. doi:10.2174/1568026023393525. PMID 12171573. "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.". 
  56. ↑ Morris H (9 January 2018). "A Fungal Fairy Tale". Hamilton's Pharmacopeia. Season 2. Episode 7. Vice Media. Viceland.
  57. ↑ "Fungal hallucinogens psilocin, ibotenic acid, and muscimol: analytical methods and biologic activities". Ther Drug Monit 35 (4): 420–442. August 2013. doi:10.1097/FTD.0b013e31828741a5. PMID 23851905. 
  58. ↑ "GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic". Biochem Pharmacol 68 (8): 1573–1580. October 2004. doi:10.1016/j.bcp.2004.06.040. PMID 15451401. 
  59. ↑ "Emerging Risks of Amanita Muscaria: Case Reports on Increasing Consumption and Health Risks". Acta Med Litu 32 (1): 182–189. 2025. doi:10.15388/Amed.2025.32.1.23. PMID 40641545. 
  60. ↑ "Exploring User Experiences with Amanita muscaria: A Thematic Analysis of Reddit Online Forum Discussions". Subst Use Misuse 60 (7): 952–961. 2025. doi:10.1080/10826084.2025.2476141. PMID 40057818. "The commonly reported reason for Amanita muscaria use was to improve sleep.". 
  61. ↑ 61.0 61.1 "Sodium oxybate: a potential new pharmacological option for the treatment of fibromyalgia syndrome". Ther Adv Musculoskelet Dis 3 (4): 167–178. August 2011. doi:10.1177/1759720X11411599. PMID 22870476. "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.". 
  62. ↑ 62.0 62.1 "Effects of oxybate dose and regimen on disrupted nighttime sleep and sleep architecture". Sleep Med 114: 255–265. February 2024. doi:10.1016/j.sleep.2023.12.015. PMID 38244463. 
  63. ↑ "Slow-wave sleep deficiency and enhancement: implications for insomnia and its management". World J Biol Psychiatry 11 Suppl 1: 22–28. June 2010. doi:10.3109/15622971003637645. PMID 20509829. "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).". 
  64. ↑ 64.0 64.1 64.2 "Can Slow-Wave Sleep Enhancement Improve Memory? A Review of Current Approaches and Cognitive Outcomes". Yale J Biol Med 92 (1): 63–80. March 2019. PMID 30923474. 
  65. ↑ "Sodium oxybate for narcolepsy". Expert Rev Neurother 6 (8): 1139–1146. August 2006. doi:10.1586/14737175.6.8.1139. PMID 16893342. 
  66. ↑ "Sodium oxybate therapy provides multidimensional improvement in fibromyalgia: results of an international phase 3 trial". Ann Rheum Dis 71 (6): 935–942. June 2012. doi:10.1136/annrheumdis-2011-200418. PMID 22294641. 
  67. ↑ 67.0 67.1 "Nonrestorative sleep: symptom or unique diagnostic entity?". Sleep Med 13 (6): 561–569. June 2012. doi:10.1016/j.sleep.2012.02.002. PMID 22560828. 
  68. ↑ "Nonrestorative sleep". Sleep Med Rev 12 (4): 275–288. August 2008. doi:10.1016/j.smrv.2007.12.002. PMID 18539057. 
  69. ↑ 69.0 69.1 69.2 69.3 Lee, Elliott K; Auger, R. Robert (23 April 2024). "Sleep and Long COVID—A Review and Exploration of Sleep Disturbances in Post Acute Sequelae of SARS-COV-2 (PASC) and Therapeutic Possibilities". Current Sleep Medicine Reports 10 (2): 169–180. doi:10.1007/s40675-024-00299-4. ISSN 2198-6401. https://link.springer.com/10.1007/s40675-024-00299-4. Retrieved 29 September 2025. 
  70. ↑ "Treatment of the narcoleptiform sleep disorder in chronic fatigue syndrome and fibromyalgia with sodium oxybate". Pain Pract 10 (1): 54–59. 2010. doi:10.1111/j.1533-2500.2009.00334.x. PMID 20629967. 
  71. ↑ "Clinical applications of sodium oxybate (GHB): from narcolepsy to alcohol withdrawal syndrome". Eur Rev Med Pharmacol Sci 19 (23): 4654–4563. December 2015. PMID 26698265. 
  72. ↑ "γ-Hydroxybutyric Acid: Pharmacokinetics, Pharmacodynamics, and Toxicology". AAPS J 23 (1). January 2021. doi:10.1208/s12248-020-00543-z. PMID 33417072. 
  73. ↑ 73.0 73.1 73.2 "A review of sodium oxybate and baclofen in the treatment of sleep disorders". Curr Pharm Des 17 (15): 1430–1435. 2011. doi:10.2174/138161211796197098. PMID 21476957. 
  74. ↑ 74.0 74.1 74.2 74.3 "International Union of Basic and Clinical Pharmacology. CXX. γ-Hydroxybutyrate protein targets in the mammalian brain-beyond classic receptors". Pharmacol Rev 77 (4). July 2025. doi:10.1016/j.pharmr.2025.100064. PMID 40449125. 
  75. ↑ 75.0 75.1 "Classics in Chemical Neuroscience: Baclofen". ACS Chem Neurosci 11 (12): 1740–1755. June 2020. doi:10.1021/acschemneuro.0c00254. PMID 32436697. 
  76. ↑ Kothare, Sanjeev V.; Kaleyias, Joseph (2010). "Pharmacotherapy of Narcolepsy: Focus on Sodium Oxybate". Clinical Medicine Insights: Therapeutics 2. doi:10.4137/CMT.S1087. ISSN 1179-559X. 
  77. ↑ 77.0 77.1 77.2 77.3 "Enhancement of slow wave sleep: implications for insomnia". J Clin Sleep Med 5 (2 Suppl): S27–32. April 2009. doi:10.5664/jcsm.5.2S.S27. PMID 19998872. 
  78. ↑ "Tiagabine in anxiety disorders". Expert Opin Pharmacother 7 (14): 1977–1987. October 2006. doi:10.1517/14656566.7.14.1977. PMID 17020423. 
  79. ↑ "Tiagabine pharmacology in profile". Epilepsia 36 Suppl 6: S7–S9. 1995. doi:10.1111/j.1528-1157.1995.tb06015.x. PMID 8595791. 
  80. ↑ "Emerging pharmacotherapeutic agents for insomnia: a hypnotic panacea?". Expert Opin Pharmacother 7 (13): 1731–1738. September 2006. doi:10.1517/14656566.7.13.1731. PMID 16925500. "In 2005, the FDA announced that a bolded warning would be added to the labelling for tiagabine, to inform prescribers of the risk of seizures in those without epilepsy who were being treated with the medication; therefore, off-label use of tiagabine was discouraged.". 
  81. ↑ "Pharmacotherapy of insomnia". Expert Opin Pharmacother 13 (9): 1243–1260. June 2012. doi:10.1517/14656566.2012.683860. PMID 22578014. "5.1 Tiagabine and gaboxadol Two agents recently developed which have very distinct mechanisms of action are tiagabine (Gabitril, Cephalon [60]), which blocks synaptic GABA re-uptake, and gaboxadol, a selective extrasynaptic GABAA receptor agonist. [...] However, it should be mentioned that in 2005, the FDA issued a warning for de novo occurrence of seizures in patients without epilepsy, discouraging off-label use of this drug.". 
  82. ↑ "Gabitril (tiagabine hydrochloride) prescribing information". U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020646s021lbl.pdf. 
  83. ↑ "Melatonin as a chronobiotic". Sleep Medicine Reviews 9 (1): 25–39. February 2005. doi:10.1016/j.smrv.2004.05.002. PMID 15649736. 
  84. ↑ Liu, Jiabei; Clough, Shannon J.; Hutchinson, Anthony J.; Adamah-Biassi, Ekue B.; Popovska-Gorevski, Marina; Dubocovich, Margarita L. (2016). "MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective". Annual Review of Pharmacology and Toxicology 56: 361–383. doi:10.1146/annurev-pharmtox-010814-124742. ISSN 1545-4304. PMID 26514204. 
  85. ↑ Low, Tian Ling; Choo, Faith Nadine; Tan, Shian Ming (2020). "The efficacy of melatonin and melatonin agonists in insomnia - An umbrella review". Journal of Psychiatric Research 121: 10–23. doi:10.1016/j.jpsychires.2019.10.022. ISSN 1879-1379. PMID 31715492. 
  86. ↑ "Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders". Pharmacotherapy 36 (9): 1028–41. September 2016. doi:10.1002/phar.1822. PMID 27500861. 
  87. ↑ Culpepper, Larry; Wingertzahn, Mark A. (2015). "Over-the-Counter Agents for the Treatment of Occasional Disturbed Sleep or Transient Insomnia: A Systematic Review of Efficacy and Safety". The Primary Care Companion for CNS Disorders 17 (6). doi:10.4088/PCC.15r01798. ISSN 2155-7772. PMID 27057416. 
  88. ↑ 88.0 88.1 "Histamine-1 receptor antagonism for treatment of insomnia". J Am Pharm Assoc (2003) 52 (6): e210–e219. 2012. doi:10.1331/JAPhA.2012.12051. PMID 23229983. 
  89. ↑ 89.0 89.1 "Classics in Chemical Neuroscience: Deliriant Antihistaminic Drugs". ACS Chem Neurosci 15 (21): 3848–3862. November 2024. doi:10.1021/acschemneuro.4c00505. PMID 39404616. 
  90. ↑ "Pharmacotherapy for insomnia in adults". https://www.uptodate.com/contents/pharmacotherapy-for-insomnia-in-adults. 
  91. ↑ 91.0 91.1 91.2 91.3 "Drug-Induced Insomnia and Excessive Sleepiness". Sleep Med Clin 17 (3): 471–484. September 2022. doi:10.1016/j.jsmc.2022.06.011. PMID 36150808. 
  92. ↑ "Medications Used for Pediatric Insomnia". Child Adolesc Psychiatr Clin N Am 30 (1): 85–99. January 2021. doi:10.1016/j.chc.2020.09.001. PMID 33223070. 
  93. ↑ "Cyproheptadine: a psychopharmacological treasure trove?". CNS Spectr 27 (5): 533–535. October 2022. doi:10.1017/S1092852921000250. PMID 33632345. 
  94. ↑ Slater, J. W.; Zechnich, A. D.; Haxby, D. G. (1999). "Second-generation antihistamines: a comparative review". Drugs 57 (1): 31–47. doi:10.2165/00003495-199957010-00004. ISSN 0012-6667. PMID 9951950. 
  95. ↑ Mieda, Michihiro; Tsujino, Natsuko; Sakurai, Takeshi (2013). "Differential roles of orexin receptors in the regulation of sleep/wakefulness". Frontiers in Endocrinology 4: 57. doi:10.3389/fendo.2013.00057. ISSN 1664-2392. PMID 23730297. 
  96. ↑ "Comparative efficacy and safety of daridorexant, lemborexant, and suvorexant for insomnia: a systematic review and network meta-analysis". Transl Psychiatry 15 (1). June 2025. doi:10.1038/s41398-025-03439-8. PMID 40555730. 
  97. ↑ 97.0 97.1 97.2 97.3 97.4 97.5 "Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis". Lancet 400 (10347): 170–184. July 2022. doi:10.1016/S0140-6736(22)00878-9. PMID 35843245. 
  98. ↑ "Efficacy and Safety of Seltorexant in Insomnia Disorder: A Randomized Clinical Trial". JAMA Psychiatry 82 (10): 967–976. August 2025. doi:10.1001/jamapsychiatry.2025.1999. PMID 40802194. 
  99. ↑ 99.0 99.1 99.2 99.3 "Role of 5-HT2A receptor antagonists in the treatment of insomnia". Nat Sci Sleep 2: 139–150. 2010. doi:10.2147/nss.s6849. PMID 23616706. 
  100. ↑ 100.0 100.1 100.2 Monti, Jaime M.; Torterolo, Pablo; Spence, David Warren; Pandi-Perumal, Seithikurippu R. (6 November 2017). "Selective Serotonin 5-HT2A Receptor Antagonists and Inverse Agonists Specifically Promote Slow Wave Sleep (Stage N3) in Man". Sleep and Vigilance 2 (1): 23–31. doi:10.1007/s41782-017-0024-7. ISSN 2510-2265. https://link.springer.com/10.1007/s41782-017-0024-7. Retrieved 30 September 2025. 
  101. ↑ "Managing insomnia: an overview of insomnia and pharmacologic treatment strategies in use and on the horizon". Drugs Context 2013. October 2013. doi:10.7573/dic.212257. PMID 24432044. 
  102. ↑ 102.0 102.1 "Effects of psychiatric medications on sleep and sleep disorders". CNS Neurol Disord Drug Targets 6 (1): 17–29. February 2007. doi:10.2174/187152707779940835. PMID 17305551. 
  103. ↑ "Prescription Drugs Used in Insomnia". Sleep Med Clin 17 (3): 315–328. September 2022. doi:10.1016/j.jsmc.2022.06.001. PMID 36150797. 
  104. ↑ "Gabapentinoids: a therapeutic review". Aust Prescr 46 (4): 80–85. December 2023. doi:10.18773/austprescr.2023.025. PMID 38152314. 
  105. ↑ 105.00 105.01 105.02 105.03 105.04 105.05 105.06 105.07 105.08 105.09 105.10 105.11 105.12 105.13 "Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery". Pharmacol Rev 70 (2): 197–245. April 2018. doi:10.1124/pr.117.014381. PMID 29487083. 
  106. ↑ "Undertreatment of menopausal symptoms and novel options for comprehensive management". Curr Med Res Opin 25 (11): 2689–2698. November 2009. doi:10.1185/03007990903240519. PMID 19775194. "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.". 
  107. ↑ "PD 0299685". 5 November 2023. https://adisinsight.springer.com/drugs/800021998. 
  108. ↑ 108.0 108.1 108.2 "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". Sleep Med Rev 84. August 2025. doi:10.1016/j.smrv.2025.102156. PMID 40929927. 
  109. ↑ 109.0 109.1 109.2 "Cannabinoids, Insomnia, and Other Sleep Disorders". Chest 162 (2): 452–465. August 2022. doi:10.1016/j.chest.2022.04.151. PMID 35537535. "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.". 
  110. ↑ "Cannabidiol/tetrahydrocannabinol". 25 July 2022. https://adisinsight.springer.com/drugs/800057418. 
  111. ↑ 111.0 111.1 "New Developments in Insomnia Medications of Relevance to Mental Health Disorders". Psychiatr Clin North Am 38 (4): 843–860. December 2015. doi:10.1016/j.psc.2015.08.001. PMID 26600112. 
  112. ↑ 112.0 112.1 "Factors impacting prazosin efficacy for nightmares and insomnia in PTSD patients - a systematic review and meta-regression analysis". Prog Neuropsychopharmacol Biol Psychiatry 136. January 2025. doi:10.1016/j.pnpbp.2025.111253. PMID 39828080. 
  113. ↑ 113.0 113.1 "Pharmacotherapy for sleep disturbances in post-traumatic stress disorder (PTSD): A network meta-analysis". Sleep Med 119: 467–479. July 2024. doi:10.1016/j.sleep.2024.05.032. PMID 38795401. 
  114. ↑ 114.0 114.1 "Sleep disturbances in patients with post-traumatic stress disorder: epidemiology, impact and approaches to management". CNS Drugs 20 (7): 567–590. 2006. doi:10.2165/00023210-200620070-00003. PMID 16800716. 
  115. ↑ "Mechanism of action of antidepressant medications". J Clin Psychiatry 60 Suppl 4: 4–11; discussion 12–3. 1999. PMID 10086478. 
  116. ↑ "Antidepressants for insomnia in adults". Cochrane Database Syst Rev 2018 (5). May 2018. doi:10.1002/14651858.CD010753.pub2. PMID 29761479. 
  117. ↑ 117.0 117.1 "Synergistic sedative effects of noradrenergic alpha(1)- and beta-receptor blockade on forebrain electroencephalographic and behavioral indices". Neuroscience 99 (3): 495–505. 2000. doi:10.1016/s0306-4522(00)00215-3. PMID 11029541. 
  118. ↑ "β-Blockers and risk of neuropsychiatric disorders: A systematic review and meta-analysis". Br J Clin Pharmacol 91 (2): 325–337. February 2025. doi:10.1111/bcp.16361. PMID 39658346. 
  119. ↑ "Neuropsychiatric Consequences of Lipophilic Beta-Blockers". Medicina (Kaunas) 57 (2): 155. February 2021. doi:10.3390/medicina57020155. PMID 33572109. 
  120. ↑ "Lack of sleep-inducing properties of propranolol (80 mg) in chronic insomniacs previously treated by common hypnotic medications". Int Clin Psychopharmacol 2 (2): 135–140. April 1987. doi:10.1097/00004850-198704000-00007. PMID 3298418. 
  121. ↑ "β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon". J Cardiovasc Pharmacol Ther 22 (3): 239–249. May 2017. doi:10.1177/1074248416681644. PMID 28399647. 
  122. ↑ Pagel, J. F.; Pandi-Perumal, Seithikurippu R.; Monti, Jaime M. (2018). "Treating insomnia with medications". Sleep Science and Practice 2 (1). doi:10.1186/s41606-018-0025-z. ISSN 2398-2683. "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).". 
  123. ↑ 123.0 123.1 "Safety, Tolerability and Efficacy of Drugs for Treating Behavioural Insomnia in Children with Attention-Deficit/Hyperactivity Disorder: A Systematic Review with Methodological Quality Assessment". Paediatr Drugs 19 (3): 235–250. June 2017. doi:10.1007/s40272-017-0224-6. PMID 28391425. 
  124. ↑ 124.0 124.1 "Pharmacological management for insomnia in children and adolescents with autism and attention deficit and hyperactivity disorder". Expert Opin Pharmacother 26 (9): 1079–1098. June 2025. doi:10.1080/14656566.2025.2508277. PMID 40400273. 
  125. ↑ "A review of the use of clonidine as a sleep aid in the child and adolescent population". Clin Pediatr (Phila) 53 (3): 211–216. March 2014. doi:10.1177/0009922813502123. PMID 24027233. 
  126. ↑ 126.0 126.1 126.2 "Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine". Clin Pharmacokinet 56 (8): 893–913. August 2017. doi:10.1007/s40262-017-0507-7. PMID 28105598. 
  127. ↑ "The alpha2-adrenoceptor agonist dexmedetomidine converges on an endogenous sleep-promoting pathway to exert its sedative effects". Anesthesiology 98 (2): 428–436. February 2003. doi:10.1097/00000542-200302000-00024. PMID 12552203. 
  128. ↑ "Electroencephalogram spindle activity during dexmedetomidine sedation and physiological sleep". Acta Anaesthesiologica Scandinavica 52 (2): 289–294. February 2008. doi:10.1111/j.1399-6576.2007.01537.x. PMID 18005372. 
  129. ↑ 129.0 129.1 "Tasipimidine-the pharmacological profile of a novel orally active selective α2A-adrenoceptor agonist". Eur J Pharmacol 923. May 2022. doi:10.1016/j.ejphar.2022.174949. PMID 35405115. 
  130. ↑ "Tasipimidine". 28 October 2024. https://adisinsight.springer.com/drugs/800070674. 
  131. ↑ "alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role". Anaesthesia 54 (2): 146–165. February 1999. doi:10.1046/j.1365-2044.1999.00659.x. PMID 10215710. 
  132. ↑ "Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale". Yale J Biol Med 85 (1): 45–58. March 2012. PMID 22461743. 
  133. ↑ 133.0 133.1 133.2 133.3 "Oral nonprescription treatment for insomnia: an evaluation of products with limited evidence". J Clin Sleep Med 1 (2): 173–187. April 2005. doi:10.5664/jcsm.26314. PMID 17561634. 
  134. ↑ 134.0 134.1 "L-tryptophan: a rational anti-depressant and a natural hypnotic?". Aust N Z J Psychiatry 22 (1): 83–97. March 1988. doi:10.1080/00048678809158946. PMID 3285826. 
  135. ↑ "Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders". Drugs & Aging 4 (4): 331–355. April 1994. doi:10.2165/00002512-199404040-00006. PMID 8019056. 
  136. ↑ "Levate (amitriptyline), dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. http://reference.medscape.com/drug/levate-amitriptyline-342936#showall. 
  137. ↑ "Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study". The Journal of Clinical Psychiatry 62 (6): 453–463. June 2001. doi:10.4088/JCP.v62n0609. PMID 11465523. 
  138. ↑ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. https://archive.org/details/bnf65britishnati0000unse. 
  139. ↑ "Mirtazapine: a newer antidepressant". American Family Physician 59 (1): 159–161. January 1999. PMID 9917581. 
  140. ↑ "Insomnia in patients with depression: some pathophysiological and treatment considerations". CNS Drugs 23 (4): 309–329. 2009. doi:10.2165/00023210-200923040-00004. PMID 19374460. 
  141. ↑ "Efficacy and side effects of mianserin, a tetracyclic antidepressant". Postgraduate Medical Journal 59 (690): 229–231. April 1983. doi:10.1136/pgmj.59.690.229. PMID 6346303. 
  142. ↑ 142.0 142.1 "Antipsychotic Drug-Induced Somnolence: Incidence, Mechanisms, and Management". CNS Drugs 30 (9): 845–867. September 2016. doi:10.1007/s40263-016-0352-5. PMID 27372312. 
  143. ↑ "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet 382 (9896): 951–962. September 2013. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. 
  144. ↑ "Quetiapine for primary insomnia: Consider the risks". Cleve Clin J Med 88 (5): 286–294. May 2021. doi:10.3949/ccjm.88a.20031. PMID 33941603. 
  145. ↑ Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Reviews, No. 43. Rockville: Agency for Healthcare Research and Quality. 2011. 
  146. ↑ "Safety of low doses of quetiapine when used for insomnia". The Annals of Pharmacotherapy 46 (5): 718–722. May 2012. doi:10.1345/aph.1Q697. PMID 22510671. 
  147. ↑ Højlund M (2022-09-12). Low-dose Quetiapine: Utilization and Cardiometabolic Risk (Ph.D. thesis). University of Southern Denmark. doi:10.21996/mr3m-1783.
  148. ↑ "Use of low-dose quetiapine increases the risk of major adverse cardiovascular events: results from a nationwide active comparator-controlled cohort study". World Psychiatry 21 (3): 444–451. October 2022. doi:10.1002/wps.21010. PMID 36073694. 
  149. ↑ "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". The Lancet. Psychiatry 7 (1): 64–77. January 2020. doi:10.1016/s2215-0366(19)30416-x. PMID 31860457. 
  150. ↑ "Dose-dependent effects of antipsychotics on efficacy and adverse effects in schizophrenia". Behavioural Brain Research 402. March 2021. doi:10.1016/j.bbr.2020.113098. PMID 33417992. 
  151. ↑ "Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis" (in English). Lancet 400 (10347): 170–184. July 2022. doi:10.1016/S0140-6736(22)00878-9. PMID 35843245. 
  152. ↑ "Medicinal plants for insomnia: a review of their pharmacology, efficacy and tolerability". J Psychopharmacol 19 (4): 414–421. July 2005. doi:10.1177/0269881105053309. PMID 15982998. 
  153. ↑ "Herbal medicine for insomnia: A systematic review and meta-analysis". Sleep Med Rev 24: 1–12. December 2015. doi:10.1016/j.smrv.2014.12.003. PMID 25644982. 
  154. ↑ "The Impact of Complementary and Alternative Medicine on Insomnia: A Systematic Review". Cureus 14 (8). August 2022. doi:10.7759/cureus.28425. PMID 36176875. 
  155. ↑ "Does valerian work for insomnia? An umbrella review of the evidence". Eur Neuropsychopharmacol 82: 6–28. May 2024. doi:10.1016/j.euroneuro.2024.01.008. PMID 38359657. 
  156. ↑ "Histamine in the regulation of wakefulness". Sleep Med Rev 15 (1): 65–74. February 2011. doi:10.1016/j.smrv.2010.06.004. PMID 20851648. 
  157. ↑ "Adenosine and Sleep". Handb Exp Pharmacol. Handbook of Experimental Pharmacology 253: 359–381. 2019. doi:10.1007/164_2017_36. ISBN 978-3-030-11270-7. PMID 28646346. 
  158. ↑ "The mechanism study of YZG-331 on sedative and hypnotic effects". Behav Brain Res 428. June 2022. doi:10.1016/j.bbr.2022.113885. PMID 35398229. 
  159. ↑ "The involvement of dopamine in the modulation of sleep and waking". Sleep Med Rev 11 (2): 113–133. April 2007. doi:10.1016/j.smrv.2006.08.003. PMID 17275369. 
  160. ↑ "Selective alterations of the first NREM sleep cycle in humans by a dopamine D1 receptor antagonist (NNC-687)". J Psychiatr Res 37 (4): 305–312. 2003. doi:10.1016/s0022-3956(03)00007-4. PMID 12765853. 
  161. ↑ Xu, Chong; Leung, Janice Ching Nam; Shi, Jiaying; Lum, Dawn Hei; Lai, Francisco Tsz Tsun (February 2024). "Sedative-hypnotics and osteoporotic fractures: A systematic review of observational studies with over six million individuals" (in en). Sleep Medicine Reviews 73. doi:10.1016/j.smrv.2023.101866. PMID 37926010. https://linkinghub.elsevier.com/retrieve/pii/S1087079223001223. 
  162. ↑ Citation error. See the inline comment on how to fix it.
  163. ↑ "Insomnia in older adults: A review of treatment options". Cleve Clin J Med 92 (1): 43–50. January 2025. doi:10.3949/ccjm.92a.24073. PMID 39746731. 
  164. ↑ Pacific Record of Medicine and Surgery - Volume 5 - Page 36 1890
  165. ↑ 165.0 165.1 "Benzodiazepines". A Historical Dictionary of Psychiatry. Oxford University Press. 2005. pp. 41–2. ISBN 978-0-19-517668-1. https://books.google.com/books?id=M49pEDoEpl0C&pg=PA41. Retrieved 2014-02-06. 
  166. ↑ "Barbiturates". http://www.ch.ic.ac.uk/rzepa/mim/drugs/html/barbiturate_text.htm. 
  167. ↑ "Suicide in Brisbane, 1956 to 1973: the drug-death epidemic". The Medical Journal of Australia 1 (24): 737–743. June 1975. doi:10.5694/j.1326-5377.1975.tb111781.x. PMID 239307. 
  168. ↑ "Sleep and hypnotic drugs". Drugs 9 (6): 448–478. 1975. doi:10.2165/00003495-197509060-00004. PMID 238826. 
  169. ↑ "[New hypnotics: perspectives from sleep physiology]". Vertex 18 (74): 294–299. July–August 2007. PMID 18265473. 
  170. ↑ "Synthetic Approaches Towards Quinazolines, Quinazolinones and Quinazolinediones on Solid Phase". QSAR & Combinatorial Science 23 (6): 440–459. July 2004. doi:10.1002/qsar.200420018. ISSN 1611-020X. 
  171. ↑ "Benefit-risk assessment of zaleplon in the treatment of insomnia". Drug Safety 28 (4): 301–318. 2005. doi:10.2165/00002018-200528040-00003. PMID 15783240. 
  172. ↑ "The orexin story and orexin receptor antagonists for the treatment of insomnia". J Sleep Res 32 (6). December 2023. doi:10.1111/jsr.13902. PMID 37086045. 

Further reading



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Hypnotic&oldid=4358670"