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Hypnotic
Drug class
Zolpidem tablets, a common but potent hypnotic used for insomnia.
Class identifiers
SynonymsSedative; Somnifacient; Soporific; Sleeping pill; Sleep aid; Sedative–hypnotic; Hypnotica
UseInsomnia, hypersomnia, narcolepsy
Mechanism of actionVarious
Biological targetVarious
Chemical classVarious
Legal status
Legal status
  • Variable
In Wikidata

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

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GABAA receptor positive allosteric modulators

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Main article: GABAA receptor positive allosteric modulator

Benzodiazepines

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Main article: Benzodiazepine § Insomnia

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

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Main article: 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.[failed verification] A different team was more skeptical, finding little benefit over benzodiazepines.[29]

Barbiturates

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Main article: 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

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Main articles: 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

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Main article: 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

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See also: Sleep induction § Alcohol

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

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Main article: GABAA receptor agonist

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

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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

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Main article: GABA reuptake inhibitor

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 several cognitive outcomes.[77][64] The drug has an elimination half-life of 5 to 8 hours.[79]

Melatonin receptor agonists

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Main article: 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.[80] It activates the melatonin MT1 and MT2 receptors to produce beneficial effects on sleep, therefore being used exogenously for mild insomnia.[81] A small improvement in sleep onset and total sleep time by using melatonin has been shown in recent systematic reviews.[82] 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.[83]

Histamine H1 receptor antagonists

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Main article: 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.[citation needed] 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.[84] Many sedating antihistamines also have anticholinergic activity that can produce side effects like cognitive impairment.[85][86] Low-dose doxepin (Silenor) is approved by the FDA for the treatment of insomnia.[87] 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.[85][88][89][90] 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.[91]

Orexin receptor antagonists

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Main article: Orexin antagonist

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.[92] 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.[93][94][95]

Serotonin 5-HT2A receptor antagonists

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Serotonin 5-HT2A receptor antagonists such as ritanserin, ketanserin, eplivanserin, volinanserin, nelotanserin, and pimavanserin have been studied and developed to improve sleep.[96][97] They do not improve sleep onset, but have been found to increase slow wave sleep (deep sleep) and reduce nighttime awakenings.[96][97] Conversely, improvement in subjective sleep ratings have been more mixed.[96] Ultimately no selective serotonin 5-HT2A receptor antagonists have been approved for treatment of insomnia.[96] The only selective serotonin 5-HT2A receptor antagonist to be approved for any indication is pimavanserin for treatment of Parkinson's disease psychosis.[97] 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.[98][99][100][88][86]

Gabapentinoids

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Main article: Gabapentinoid

Gabapentinoids, also known as α2δ subunit-containing voltage-gated calcium channel ligands, include drugs like gabapentin, pregabalin, and gabapentin enacarbil.[101] They have been found to increase slow wave sleep (deep sleep) in people with insomnia and healthy individuals.[102][99] However, they do not appear to improve sleep onset.[102] The gabapentinoid atagabalin (PD-0200390) was under formal development for treatment of insomnia, but development was discontinued following unsatisfactory clinical trial results.[102] 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.[103][104]

Cannabinoids

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Main articles: 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.[105][106] They have been found to improve sleep onset, sleep duration, and sleep quality.[105][106] Cannabidiol (CBD), which acts differently than other cannabinoids like THC, is not effective in improving sleep on the other hand.[105] Zenivol is a cannabis extract which is approved for the treatment of insomnia in Germany.[107][106]

α1- and β-adrenergic receptor antagonists

[edit]
Main articles: 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).[108][109][110][111] It is clinically effective for this purpose.[109][110][111] However, the drug is also an antihypertensive agent and can lower blood pressure, thereby producing side effects like dizziness and orthostatic hypotension.[108] Certain non-selective hypnotics such as trazodone and tricyclic antidepressants (TCAs) like amitriptyline and trimipramine are also α1-adrenergic receptor antagonists.[102][112][113] 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.[102][114] Conversely, timolol alone produced no such effects.[102][114] 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.[115][116][117] 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.[88][118][119] However, these two beta blockers have also been associated with insomnia similarly to selective beta blockers.[88]

α2-Adrenergic receptor agonists

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α2-Adrenergic receptor agonists like clonidine can improve sleep and may be useful in the treatment of insomnia.[102][120][121] 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.[120][121][122] Similarly to clonidine, the α2-adrenergic receptor agonist dexmedetomidine has sedative and hypnotic effects and is used to produce sedation in hospital settings.[123] The sleep induced by dexmedetomidine is said to closely resemble natural sleep.[123][124][125] 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.[126][127] α2-Adrenergic receptor agonists can produce hypotension and bradycardia as side effects, which has limited their use.[128][123] Activation of the α2A-adrenergic receptor is thought to be responsible for most of the physiological effects of the α2-adrenergic receptors, including hypotension.[126] On the other hand, the preferential α2A-adrenergic receptor agonist guanfacine appears to show less sedation and hypotension than clonidine.[129]

Serotonin precursors

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The serotonin precursors tryptophan and 5-hydroxytryptophan (5-HTP; oxitriptan) are available as over-the-counter supplements.[130][131] They are often used to produce sleepiness and treat insomnia.[130][131] However, little to no clinical data exist to support their use or effectiveness.[130]

Multiple mechanisms

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Antidepressants

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Some antidepressants have hypnotic and/or sedative effects.[102] These include the serotonin antagonist and reuptake inhibitor (SARI) trazodone,[132] tricyclic antidepressants (TCAs) such as amitriptyline,[133] doxepin,[134] and trimipramine,[135] and tetracyclic antidepressants (TeCAs) like mirtazapine[136][137] and mianserin.[138][102] 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.[102] 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

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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.[139][140] However, the most commonly used agents for insomnia are quetiapine and olanzapine.[102][141] 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.[102][139] 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.[142][143] 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,[144][145][146][147] 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.[148]

Herbal supplements

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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.[149][150][151][130][152]

Other drugs

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Various other types of drugs have also been found to produce hypnotic-type effects in scientific research.[102] Examples include histamine H3 receptor agonists like α-methylhistamine, BP 2.94, GT-2203 (VUF-5296), and SCH-50971,[153] adenosine A1 and A2A receptor agonists like adenosine and YZG-331,[154][102][155] and dopamine D1 receptor receptor antagonists like NNC 01-0687 (ADX-10061, CEE-03-310, NNC-687).[156][157]

Comparative effectiveness

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A major systematic review and network meta-analysis of medications for the treatment of insomnia was published in 2022.[94] It found a widely varying range of effect sizes (standardized mean difference or SMD) in terms of clinical effectiveness for insomnia.[94] 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).[94] The certainty of evidence varied and ranged from high to very low depending on the medication.[94] 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.[94]

Risks

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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.[158] 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).[159] 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] Some hypnotics, such as low-dose doxepin, melatonin receptor agonists, and orexin receptor antagonists, may be safer and more appropriate in older adults however.[160]

History

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Le Vieux Séducteur by Charles Motte [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.[161]

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.[162] Barbiturates emerged as the first class of drugs in the early 1900s,[163] 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.[164][165][166]

During the 1970s, quinazolinones[167] and benzodiazepines were introduced as safer alternatives to replace barbiturates; by the late 1970s, benzodiazepines emerged as the safer drug.[162]

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.[168]

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.[169]

See also

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Notes

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References

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Further reading

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A hypnotic is a type of psychoactive primarily used to induce and maintain , distinguishing it from broader sedatives that mainly calm or reduce anxiety. These drugs, also referred to as soporifics, work by depressing activity to promote drowsiness and facilitate the onset and maintenance of . Hypnotics are commonly prescribed for short-term management of and other sleep disturbances, though they are also employed in procedural , such as for patients on . The development of hypnotic drugs spans over a century, beginning with barbiturates introduced in the early 1900s as the first widely used class for and . By the to mid-1950s, barbiturates dominated hypnotic therapy due to their effectiveness in treating , anxiety, and seizures, though their narrow led to risks of overdose. Benzodiazepines emerged in the , offering safer profiles with reduced lethality in overdose, and became the standard for treatment by the 1970s. More recent innovations include non-benzodiazepine "Z-drugs" starting in the 1990s, agonists, and antagonists, reflecting ongoing efforts to minimize side effects while targeting pathways more selectively. Hypnotics are classified into several major categories based on and mechanism: barbiturates (e.g., ), benzodiazepines (e.g., , ), non-benzodiazepine agonists or Z-drugs (e.g., , , ), melatonin receptor agonists (e.g., ), and dual antagonists (e.g., ). Most act by enhancing the inhibitory effects of gamma-aminobutyric acid (GABA), the brain's primary inhibitory , through binding to s, which increases chloride influx and hyperpolarizes neurons to suppress excitability. Newer agents like antagonists instead block wake-promoting pathways in the brain. Despite their utility, hypnotics carry significant risks, including tolerance, , and withdrawal symptoms upon discontinuation, particularly with prolonged use. Common side effects encompass next-day drowsiness, , , and coordination problems, elevating the of falls and accidents, especially in older adults. More severe concerns include complex sleep-related behaviors (e.g., with potential for ), increased susceptibility, and associations with higher mortality rates, depression, and certain cancers in chronic users. Regulatory bodies emphasize short-term use and caution against combining with alcohol or opioids due to amplified respiratory depression.

Definition and Uses

Definition

Hypnotics are a class of psychoactive drugs that induce and maintain sleep by depressing the activity of the (CNS). They are primarily employed for the short-term management of , helping to facilitate the onset and duration of sleep in individuals experiencing sleep disturbances. Hypnotics differ from sedatives, which primarily reduce anxiety and excitability without reliably producing sleep, and from general anesthetics, which induce a profound state of reversible only with medical intervention, often for surgical procedures. While sedatives calm the mind and body to promote relaxation, hypnotics specifically target sleep induction, and general anesthetics suppress consciousness more completely than either. The term "hypnotic" originates from the Greek word hypnos, meaning , reflecting their role in promoting a sleep-like state; pharmacologically, they are classified as sedative-hypnotics due to their overlapping effects on CNS depression. These agents typically enhance gamma-aminobutyric acid (GABA) transmission—the brain's principal inhibitory —or modulate other inhibitory pathways to reduce neuronal excitability and foster drowsiness.

Primary Uses

Hypnotics are primarily used in the clinical management of , a characterized by difficulty initiating (sleep onset insomnia), maintaining throughout the night (sleep maintenance insomnia), or experiencing early morning awakenings with inability to return to (early awakening insomnia). These medications help reduce the time to fall asleep and increase total duration in affected individuals. According to the (AASM) clinical practice guideline, hypnotics such as are recommended for treating both sleep onset and maintenance insomnia in adults, based on evidence from randomized controlled trials demonstrating improvements in these parameters compared to . The AASM and other authoritative bodies emphasize short-term use of hypnotics, typically limited to 7-10 days, to minimize risks of tolerance, dependence, and adverse effects while addressing acute symptoms. This duration aligns with FDA approvals for many agents, ensuring benefits outweigh potential harms in . Hypnotics play a key role in managing transient and short-term insomnia, which often arises from situational factors such as acute stress, , or disrupting circadian rhythms. In these cases, short-term administration can restore normal patterns without long-term intervention. For instance, agents like are suitable for transient insomnia due to their short , allowing use for sleep onset issues without residual effects. To optimize and , hypnotics are administered immediately before , with patients advised to allow at least 7-8 hours for to reduce next-day impairment such as drowsiness or cognitive deficits. The FDA has updated dosing recommendations for several hypnotics to lower bedtime doses in certain populations, thereby mitigating residual sedation. Hypnotics are positioned as adjunctive therapy rather than first-line treatment; sleep hygiene practices—such as maintaining a consistent , avoiding stimulants, and creating a conducive sleep environment—are recommended initially, with pharmacologic intervention reserved for cases where non-pharmacologic approaches are insufficient. The AASM guideline underscores (CBT-I) as the preferred primary treatment, with hypnotics integrated only when necessary to support overall management.

Secondary Uses

Hypnotics, particularly benzodiazepines, are employed in the management of anxiety disorders as adjunctive sedatives to alleviate acute symptoms and facilitate calming effects in clinical settings. For instance, short-acting benzodiazepines such as and are commonly administered for preoperative sedation to reduce patient anxiety prior to surgical procedures, providing anxiolysis and without significant respiratory depression when dosed appropriately. In alcohol withdrawal syndrome, benzodiazepines like and chlordiazepoxide serve as first-line agents to prevent seizures and mitigate severe agitation by cross-tolerating with alcohol's effects on the . Beyond direct anxiolysis, hypnotics play an adjunctive role in conditions where sleep disruption exacerbates symptoms, such as management and . In , agents like or low-dose benzodiazepines may be prescribed off-label to improve sleep quality and indirectly enhance , though guidelines emphasize short-term use to avoid dependency. For , benzodiazepines such as were historically used to promote sleep continuity by suppressing periodic limb movements and reducing associated , but the 2024 (AASM) clinical practice guideline conditionally recommends against their use due to very low certainty of evidence and risks of adverse effects. Certain barbiturates have a historical role in treatment for control, particularly in refractory cases or . , for example, remains a standard in resource-limited settings due to its broad-spectrum efficacy in suppressing neuronal excitability, though its use has declined in favor of newer agents owing to cognitive side effects. Emerging investigational applications include the use of hypnotics in (ICU) settings for managing and procedural , tempered by risks of prolonged and . Sedatives such as benzodiazepines and are used for in ventilated s to manage agitation, but evidence highlights benzodiazepines' potential to exacerbate , prompting 2025 Society of Critical Care Medicine (SCCM) guidelines favoring non-benzodiazepine alternatives like or to reduce risk. In procedural , and provide rapid-onset for minor interventions, enabling comfort while minimizing recovery time, with monitoring essential to avert oversedation. Orexin receptor antagonists show preliminary promise in disorders by stabilizing sleep-wake cycles without the hangover effects of traditional hypnotics.

Types of Hypnotics

Barbiturates

Barbiturates represent an early class of sedative-hypnotic agents derived from , a formed from and . These drugs feature a core ring structure with two carbonyl groups at positions 2 and 4, and variations at the 5-position determine their duration of action, such as ethyl and phenyl substituents in or ethyl and 1-methylbutyl in . Common examples include (a long-acting barbiturate), secobarbital (intermediate-acting), and (short- to intermediate-acting), which were among the first synthetically developed for clinical use. Barbiturates gained historical prominence in the early following the synthesis of in 1903 by and Joseph von Mering, marking the introduction of the first marketed for therapeutic and . By the 1920s and 1930s, they became widely prescribed for , anxiety, and preoperative , supplanting earlier agents like due to their reliability in inducing . Their use expanded rapidly, with dozens of derivatives produced by pharmaceutical companies, reflecting their central role in until the mid-20th century. Today, barbiturates have limited application as hypnotics owing to their narrow —the ratio of toxic to effective dose—which heightens overdose risk and limits safe dosing margins. They are primarily reserved for insomnia cases unresponsive to safer alternatives or for therapy in conditions like , where their properties aid in control. Regulatory bodies, including the FDA, have curtailed their hypnotic indications, favoring benzodiazepines and other agents with broader safety profiles. A key pharmacokinetic characteristic of barbiturates is their variable elimination half-lives, ranging from 15–40 hours for short-acting types like to 53–118 hours (2–6 days) for long-acting ones like , which promotes drug accumulation with repeated dosing. This prolonged clearance contributes to residual sedative effects, often manifesting as next-day symptoms such as drowsiness, impaired cognition, and psychomotor deficits. Barbiturates enhance GABA_A receptor activity to produce these hypnotic outcomes, though their non-selective binding increases toxicity potential.

Benzodiazepines

Benzodiazepines represent a major class of hypnotics that enhance the activity of the neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system. These agents are particularly effective for short-term management of insomnia due to their ability to promote sleep onset and maintenance by modulating neuronal excitability. Benzodiazepines exert their hypnotic effects by binding to a specific allosteric site on the GABA_A receptor, distinct from the GABA-binding site, which increases the receptor's affinity for GABA and potentiates chloride ion influx, leading to hyperpolarization of neurons and reduced excitability. This mechanism results in sedative properties without directly activating the receptor, distinguishing them from barbiturates. Benzodiazepines used as hypnotics are classified by their duration of action, primarily based on elimination , which influences their suitability for sleep onset versus maintenance . Short-acting agents like have half-lives of 1.5–5.5 hours, making them ideal for sleep initiation without significant next-day residual effects. Intermediate-acting options, such as (half-life ~8–22 hours) and (half-life ~10–24 hours), balance efficacy for both onset and maintenance while minimizing accumulation. Long-acting benzodiazepines, including (half-life 40–100 hours due to active metabolites), provide sustained effects but carry a higher of daytime . The following table summarizes key examples of benzodiazepine hypnotics, their durations, typical half-lives, and dosing ranges for adults with :
DrugDurationHalf-Life (hours)Typical Dose (mg at bedtime)Formulation
Short1.5–5.50.125–0.25 (max 0.5)Immediate-release tablets
Intermediate8–227.5–30Immediate-release capsules
Intermediate10–241–2Immediate-release tablets
Long40–10015–30Immediate-release capsules
Doses are lower for elderly patients (e.g., starting at half the dose) to account for prolonged half-lives and increased sensitivity. Immediate-release formulations are standard for rapid onset, typically within 30–60 minutes, to align with bedtime administration. In the United States, benzodiazepines are classified as Schedule IV controlled substances under the due to their potential for abuse and dependence, necessitating prescriptions and monitoring for misuse. Chronic use can lead to tolerance, requiring dose adjustments over time.

Nonbenzodiazepines

Nonbenzodiazepines, commonly referred to as Z-drugs, represent a class of hypnotic agents developed in the late to target with greater specificity than traditional benzodiazepines. These compounds, including , , , and , act as positive allosteric modulators primarily selective for the α1 subunit of GABA_A receptors, which are predominantly located in regions associated with initiation. This subtype selectivity aims to enhance hypnotic effects while minimizing interactions with other GABA_A receptor subtypes that contribute to , , or actions seen with benzodiazepines, which bind more broadly across α1, α2, α3, and α5 subunits. The U.S. (FDA) began approving Z-drugs in the 1990s as safer alternatives for short-term treatment. received FDA approval in 1992 for onset difficulties, followed by in August 1999, which targets both sleep initiation and middle-of-the-night awakenings due to its ultrashort duration. , the active S-isomer of , was approved in December 2004 for both onset and maintenance. itself is not FDA-approved in the United States but has been available internationally since the 1980s for similar indications. A key advantage of Z-drugs over benzodiazepines lies in their pharmacokinetic profiles, featuring shorter elimination half-lives that reduce residual effects and next-day impairment. For instance, has an elimination half-life of approximately 1 hour, allowing for rapid clearance and minimal effects, making it suitable for patients needing soon after dosing. and exhibit half-lives of about 2.5 hours and 6 hours, respectively, still shorter than many benzodiazepines, thereby limiting cognitive and psychomotor deficits the following day. To address sleep maintenance issues, extended-release formulations were introduced, such as extended-release approved by the FDA in 2005, which provides biphasic release for prolonged efficacy without substantially extending overall exposure. These properties contribute to Z-drugs' comparable efficacy in reducing sleep latency to benzodiazepines, with potentially fewer spillover effects on daytime functioning. Despite their targeted design, Z-drugs carry risks of complex sleep behaviors linked to their α1 selectivity, which may disrupt normal architecture without fully suppressing pathways. The FDA issued a in 2019 for all Z-drugs, highlighting rare but serious incidents of , sleep-driving, and other unintended activities that can result in or , often occurring without full recall. This risk is attributed to the drugs' ability to induce deep sedation while preserving some ambulatory functions, contrasting with benzodiazepines' more generalized suppression.

Melatonin and Melatonin Agonists

is a naturally occurring hormone produced primarily by the that plays a key role in regulating the body's circadian rhythms and sleep-wake cycles. Synthetic receptor agonists, such as and tasimelteon, mimic this hormone's effects by selectively binding to MT1 and MT2 receptors in the of the , thereby promoting sleep onset through circadian entrainment rather than direct central nervous system depression. Unlike traditional sedatives that act on GABA receptors, these agents lack affinity for systems, reducing the risk of sedation-related side effects. Ramelteon, a highly selective MT1/MT2 with greater affinity for MT1 than itself, is approved for treating sleep-onset and has shown utility in adjusting circadian rhythms disrupted by conditions like or . The typical dose is 8 mg taken orally once daily, approximately 30 minutes before bedtime, which facilitates phase advances in circadian rhythms as demonstrated in studies using doses from 1 to 8 mg. Tasimelteon, a dual MT1/MT2 , is specifically indicated for non-24-hour sleep-wake disorder in totally blind patients, where it helps synchronize the endogenous to the 24-hour day. It is administered at a dose of 20 mg once daily, taken about one hour before bedtime at the same time each night. These agonists offer several advantages over other hypnotics, including a low potential for and dependence due to their targeted mechanism on circadian without euphoric or reinforcing effects. Clinical trials have confirmed no significant abuse liability even at supratherapeutic doses up to 20 times the recommended amount for , and neither agent is classified as a by regulatory authorities. This profile makes them particularly suitable for long-term use in circadian-related sleep disturbances.

Orexin Receptor Antagonists

Orexin receptor antagonists, commonly referred to as dual orexin receptor antagonists (DORAs), constitute a modern class of hypnotics that modulate the system to suppress wake-promoting signals in the . By targeting this pathway, DORAs offer a distinct approach to management, distinct from agents, as they inhibit arousal without broadly sedating the . The primary mechanism involves blockade of and orexin-B neuropeptides at both orexin type 1 (OX1R) and type 2 (OX2R) receptors, predominantly located on neurons in the and other centers. This inhibition reduces the activity of orexin-producing neurons, promoting the natural onset and maintenance of sleep while minimizing disruptions to sleep architecture, including stage transitions and overall sleep quality. Key examples of approved DORAs include (Belsomra), authorized by the FDA in 2014 for adults with ; (Dayvigo), approved in 2019; and (Quviviq), approved in 2022. Each of these agents competitively antagonizes both OX1R and OX2R, with dosing typically titrated to 5–20 mg for , 5–10 mg for , and 25–50 mg for to optimize efficacy while managing next-day residual effects. These medications are indicated for the treatment of chronic insomnia characterized by difficulties with onset and maintenance in adults. Clinical evidence supports their dual receptor blockade in enhancing continuity, with particular advantages in preserving rapid eye movement () sleep duration and architecture compared to traditional agonists like benzodiazepines. Post-2020 research, including randomized controlled trials, has affirmed the long-term tolerability of DORAs for up to 12 months of continuous use, showing sustained improvements in sleep parameters without physiological tolerance, withdrawal symptoms, or rebound following abrupt discontinuation. For instance, the SUNRISE 2 trial for and analogous studies for and demonstrated maintained efficacy and safety profiles over this period.

Antihistamines

First-generation antihistamines, such as diphenhydramine, , and hydroxyzine, are commonly used off-label as over-the-counter or prescription hypnotics due to their sedating properties. These agents primarily induce through blockade of central H1 , which promotes drowsiness by inhibiting wake-promoting histaminergic neurons in the ; additionally, their muscarinic receptor antagonism contributes to the overall sedative effect. Diphenhydramine and are widely available over-the-counter in many countries, often marketed under brands like for diphenhydramine and Unisom SleepTabs for doxylamine, and are indicated for short-term relief of mild . Hydroxyzine, while typically requiring a prescription, is similarly employed off-label for its hypnotic effects in managing sleep disturbances associated with anxiety or allergies. Typical dosing for these agents as hypnotics ranges from 25 to 50 mg administered at bedtime, though hydroxyzine may be dosed up to 100 mg in some cases under medical supervision. Despite their accessibility, these antihistamines carry significant limitations, particularly due to their properties, which can cause side effects such as dry mouth, , , and . In older adults, they are associated with heightened risks of , confusion, , and falls, leading to recommendations against their routine use in this population per the American Geriatrics Society Beers Criteria. Furthermore, tolerance to their hypnotic effects develops rapidly, often within days to weeks of regular use, reducing their efficacy over time. These agents may also play a secondary role in addressing issues comorbid with allergic conditions, though their primary hypnotic application remains the focus here.

Other Agents

In addition to the primary classes of hypnotics, certain antidepressants are employed off-label for their sedative properties, particularly when standard treatments prove inadequate. , a (SARI), is commonly prescribed at low doses of 50-100 mg to promote sleep onset and maintenance, owing to its blockade of 5-HT2A, H1, and alpha-1 adrenergic receptors, which collectively induce without significant next-day impairment. Similarly, , a (NaSSA), exerts hypnotic effects at low doses through potent antagonism of H1 receptors and 5-HT2A/2C receptors, enhancing while minimizing REM suppression. Low-dose , a , is FDA-approved for sleep-maintenance at doses of 3-6 mg, acting primarily through antagonism. Atypical antipsychotics, such as , are also used off-label at subtherapeutic doses (typically 25-100 mg) for , leveraging their profile derived from histamine H1 and serotonin blockade, which facilitates sleep initiation in patients with comorbid psychiatric conditions. This approach is particularly considered in cases where anxiety or agitation contributes to sleep disruption, though its routine use remains controversial due to potential metabolic risks. Among miscellaneous agents, , once a widely used hypnotic introduced in the for its rapid onset of sedation via , has largely fallen out of favor owing to evidence of carcinogenicity in and risks of toxicity, including cardiac arrhythmias. Herbal supplements like valerian root are occasionally sought for mild , purportedly through modulation of , but clinical evidence for its efficacy remains limited and inconclusive, with no FDA approval or regulation ensuring product consistency or safety. The rationale for employing these off-label agents stems from their utility in refractory insomnia, especially in patients intolerant to first-line hypnotics, but requires vigilant monitoring for adverse effects such as , , or dependency, with periodic reassessment to minimize long-term risks.

Pharmacology

Mechanisms of Action

Hypnotics primarily exert their sedative effects through enhancement of inhibitory in the , with the most common mechanism involving positive allosteric modulation of GABA_A receptors. These receptors are ligand-gated ion channels that, upon activation by the neurotransmitter gamma-aminobutyric acid (GABA), allow influx of chloride ions, leading to neuronal hyperpolarization and reduced excitability. Benzodiazepines, for example, bind at the interface between the alpha and gamma subunits of the GABA_A receptor, increasing the frequency of channel opening in the presence of GABA, thereby amplifying inhibitory signaling without directly activating the receptor. Barbiturates and nonbenzodiazepines like also target GABA_A receptors but differ in their binding sites and selectivity; , for instance, preferentially acts on alpha-1 subunit-containing receptors associated with . The potency of these agents is reflected in their dose-response relationships, where low doses produce anxiolysis and higher doses enhance by progressively increasing conductance until a maximum effect is reached, beyond which further increases may lead to general . This modulation ultimately contributes to broader by reducing neuronal firing in the reticular activating system, a network that maintains . Other classes of hypnotics target distinct pathways to promote sleep. Orexin receptor antagonists, such as , block the (hypocretin) neuropeptides that stabilize by inhibiting their binding to OX1 and OX2 receptors, thereby reducing signals from hypocretin-producing neurons in the . Melatonin receptor agonists like activate MT1 and MT2 G-protein-coupled receptors in the , inhibiting and decreasing cyclic AMP levels to phase-advance circadian rhythms and suppress neuronal firing that promotes . Antihistamines achieve sedation by antagonizing H1 receptors, which blocks histamine-mediated depolarization of postsynaptic neurons originating from the , a key that sustains vigilance during .

Pharmacokinetics and Metabolism

Hypnotic drugs, including benzodiazepines and nonbenzodiazepines, are generally characterized by rapid absorption following oral administration, which contributes to their quick onset of action for inducing sleep. For instance, zolpidem exhibits high oral bioavailability of approximately 70%, with peak plasma concentrations achieved within 0.5 to 2 hours, leading to an onset of hypnotic effects in 15 to 30 minutes. Similarly, other non-benzodiazepine hypnotics like zaleplon and eszopiclone are swiftly absorbed from the gastrointestinal tract, with bioavailability varying by agent (zolpidem approximately 70%, eszopiclone about 80%, and zaleplon around 30% due to extensive first-pass metabolism), facilitating their use for sleep initiation. This rapid absorption profile is essential for hypnotics, as it aligns with the need for prompt sedation without significant first-pass metabolism effects in the liver. Distribution of hypnotics throughout the body is influenced by their high lipophilicity, allowing efficient crossing of the blood-brain barrier to exert central nervous system effects. These agents typically have a volume of distribution ranging from 0.5 to 2 L/kg, reflecting extensive tissue penetration, particularly into lipid-rich compartments like the brain. For benzodiazepines such as diazepam, the volume of distribution is around 1-2 L/kg, enabling widespread distribution but also contributing to their accumulation in adipose tissue during repeated dosing. Protein binding varies, with zolpidem approximately 92% bound to plasma proteins, which can influence free drug availability in circulation. Metabolism of hypnotics primarily occurs in the liver, where cytochrome P450 enzymes, notably CYP3A4, play a key role in their biotransformation. Benzodiazepines like midazolam and triazolam are extensively metabolized via CYP3A4-mediated hydroxylation, producing inactive metabolites that are less likely to cause prolonged effects. In contrast, diazepam undergoes N-demethylation to form active metabolites such as nordiazepam, which extends its duration of action beyond that of the parent compound. Half-lives among hypnotics vary widely to match different therapeutic needs; for example, zaleplon has a short elimination half-life of about 1 hour, ideal for sleep onset without residual effects, while flurazepam's active metabolites have half-lives exceeding 100 hours, supporting sustained sleep maintenance but increasing the risk of accumulation. Nonbenzodiazepines like zolpidem are oxidized primarily by CYP3A4, with no active metabolites formed, resulting in a half-life of 2-3 hours. Elimination of hypnotics and their metabolites occurs mainly through renal excretion, following hepatic conjugation to water-soluble glucuronides. Most benzodiazepines are cleared renally as inactive conjugates, with less than 1-2% of the parent drug excreted unchanged in urine. Age and gender significantly influence elimination kinetics; elderly individuals experience slower clearance due to reduced hepatic metabolism and glomerular filtration rate, leading to higher plasma concentrations and prolonged half-lives compared to younger adults. For instance, zolpidem's clearance is decreased by about 30-50% in older patients, necessitating dose adjustments to avoid excessive sedation. Gender differences also exist, with women often showing slower metabolism via CYP3A4, potentially resulting in higher exposure to certain hypnotics like zopiclone.

History

Early History

The use of hypnotic agents dates back to ancient civilizations, where natural substances served as primitive sedatives to induce sleep and alleviate distress. In ancient Egypt, opium derived from the poppy plant was employed medicinally as a sedative and narcotic, with references to its application appearing in medical papyri such as the Ebers Papyrus around 1550 BCE. Similarly, alcohol was utilized in Egyptian rituals and daily life from approximately 3500 BCE, often mixed with herbs to enhance its calming effects for sleep induction. In ancient Greece, opium was widely recognized for its sleep-inducing properties, as noted by philosophers like Theophrastus, who described its use in combinations with hemlock to promote restful slumber without pain. The marked the transition to synthetic chemical hypnotics, beginning with the introduction of bromide salts as the first effective pharmacological agents for and control. In 1857, British physician Sir Charles Locock reported the and sedative effects of , initially tested on patients with and , which quickly extended its use to treating due to its calming influence on the . Bromides became a cornerstone of early psychiatric treatment, though their chronic use often led to toxicity known as . Seeking more reliable options, German pharmacologist Otto Liebreich introduced in 1869 as a novel synthetic hypnotic, synthesizing it from and and demonstrating its rapid onset of sleep in clinical trials. This compound offered a quicker and more predictable effect compared to bromides, gaining widespread adoption for and anxiety in medical practice by the 1870s. In 1882, Italian physician Vincenzo Cervello brought into clinical use, a cyclic of noted for its potent properties in treating while also exhibiting strong hypnotic and effects. Administered rectally or orally, it provided an alternative for acute agitation and sleep disturbances resistant to other agents. During this pre-barbiturate era, reliance on natural substances like and alcohol persisted alongside these emerging synthetics, particularly within the burgeoning field of , where asylums increasingly employed sedatives to manage patient excitability and promote rest amid limited therapeutic options. These developments laid the groundwork for more advanced hypnotic compounds in the .

20th Century Developments

The marked a transformative period for hypnotic drugs, with the synthesis of ushering in the era of modern for disorders. In 1903, German chemists and Josef von Mering developed , the first with significant hypnotic properties, which was patented and marketed as Veronal for its effects. quickly gained prominence as the primary class of hypnotics, reaching peak clinical use in the 1950s and 1960s for treating and anxiety, though this widespread adoption was accompanied by rising overdose epidemics due to their narrow therapeutic window and potential for fatal respiratory suppression. A pivotal advancement came with the introduction of benzodiazepines, which offered a safer alternative to barbiturates. In 1955, at Hoffmann-La Roche serendipitously synthesized chlordiazepoxide, the first , which was approved and marketed as Librium in 1960 for its and hypnotic effects with lower overdose risk. By the 1970s, benzodiazepines had supplanted barbiturates as the preferred hypnotics, attributed to their more selective enhancement of GABA-mediated inhibition, reducing the incidence of severe adverse events like from accidental overdose. Regulatory milestones shaped the development and oversight of hypnotics during this period. The thalidomide tragedy of the late 1950s and early 1960s—where the sedative, prescribed for , caused thousands of birth defects—prompted the 1962 Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act, requiring pharmaceutical companies to demonstrate both safety and efficacy through controlled clinical trials before market approval. In 1970, the established scheduling criteria based on abuse potential and medical value, classifying most barbiturates as Schedule II substances (high abuse risk with accepted use) and benzodiazepines as Schedule IV (lower abuse risk). The latter decades of the century witnessed the decline of barbiturates, fueled by accumulating evidence from neuropharmacological research on their interactions with GABA_A receptors, which underscored risks including profound , tolerance development, and in overdose scenarios. This shift paved the way for benzodiazepines and, toward the century's end, the emergence of nonbenzodiazepine "Z-drugs" as even more targeted options.

Recent Advances

In the early , advancements in non-benzodiazepine hypnotics, known as Z-drugs, addressed limitations in maintenance and long-term efficacy. , approved by the U.S. (FDA) in December 2004, marked the first hypnotic explicitly indicated for both short- and long-term treatment of , demonstrating sustained improvements in onset and total time over six months in clinical without significant tolerance development. Similarly, zolpidem extended-release formulation underwent pivotal post-2000 studies, including a 2008 randomized, double-blind showing its efficacy in reducing wake time after onset and enhancing overall quality when administered 3 to 7 nights per week for up to 24 weeks in patients with chronic primary . These developments built on earlier Z-drugs like immediate-release (approved 1992) by prioritizing formulations that better mimic natural patterns while minimizing next-day residual effects. A major shift occurred with the introduction of dual receptor antagonists (DORAs), targeting the wake-promoting system rather than the traditional pathways, amid growing concerns over benzodiazepine-related dependence, tolerance, and . , the first DORA, received FDA approval in August 2014 for characterized by difficulties with onset or maintenance, offering a novel mechanism that promotes both non-rapid (NREM) and rapid () without the disruptions seen in GABA agonists. This was followed by in December 2019 and in January 2022 (with approval in April 2022), both demonstrating comparable or superior efficacy to Z-drugs in phase III trials for efficiency, with lower risks of and next-day impairment. The transition to non-GABA mechanisms reflects a broader response to benzodiazepine backlash, emphasizing agents with reduced potential for rebound and withdrawal. Recent research trends from 2023 to 2025 highlight DORAs' advantages in preserving sleep architecture and minimizing rebound effects compared to GABAergic hypnotics. Network meta-analyses indicate that DORAs like suvorexant and lemborexant significantly improve sleep maintenance with less disruption to REM sleep and lower incidence of rebound insomnia upon discontinuation, unlike Z-drugs which may exacerbate wakefulness post-treatment in up to 20% of users. Ongoing trials, including a 2022 systematic review, underscore DORAs' role in long-term management, showing sustained efficacy over 12 months with minimal tolerance and better cognitive outcomes, positioning them as preferred options for chronic insomnia amid calls to limit GABA agents due to safety concerns. This evolution prioritizes physiological sleep promotion, with DORAs promoting natural sleep architecture including increased deep NREM and REM stages relative to some traditional hypnotics in comparative studies. As of 2025, additional developments include the approval of DORAs in new markets, such as Australia in December 2024, and studies confirming their safety profile with reduced adverse events compared to older hypnotics.

Effectiveness

Evidence from Clinical Trials

Randomized controlled trials (RCTs) from the 1980s and 1990s demonstrated that benzodiazepines, such as and , effectively reduce and increase total time in patients with . A of 45 RCTs involving 2,672 participants found that benzodiazepines decreased subjective latency by an average of 14 minutes (95% CI: 11 to 18 minutes) and increased total time by 62 minutes (95% CI: 37 to 86 minutes) compared to . These improvements were observed across short-term treatments lasting 1-4 weeks, with similar efficacy reported in trials including , showing approximately 30% reductions in latency. Non-benzodiazepine hypnotics, known as Z-drugs (e.g., , , ), exhibit efficacy comparable to benzodiazepines for improving parameters, with potentially superior tolerability profiles. A 2013 meta-analysis of FDA-submitted data from studies involving 4,378 participants indicated that Z-drugs reduced polysomnographic latency by 22 minutes (95% CI: -33 to -11 minutes) versus , though effects on total time were not significant. Updated analyses, including a 2022 of studies in older adults, confirmed similar efficacy to benzodiazepines, though long-term use is associated with increased risk of falls compared to no treatment. Orexin receptor antagonists, such as , have shown sustained in phase III trials for both sleep onset and maintenance without evidence of tolerance development. In two pivotal 3-month RCTs pooled for analysis, 20/15 mg improved and total sleep time with standardized effect sizes of 17-20% and 29-34%, respectively, compared to , with benefits persisting in a 12-month extension study where remained and no or withdrawal occurred upon discontinuation. Recent 2023-2025 reviews affirm that dual antagonists maintain beyond 6 months, distinguishing them from other hypnotics prone to tolerance. Clinical trials of hypnotics for insomnia consistently reveal a substantial placebo response, complicating the interpretation of efficacy data. Meta-analyses of placebo-controlled RCTs estimate moderate placebo effects on subjective sleep symptoms (Hedges' g = 0.27-0.58). This response underscores limitations in trial designs, as up to 63% of observed symptom relief in some pharmacotherapy studies may stem from placebo effects rather than active drug mechanisms. Clinical guidelines, such as the American Academy of Sleep Medicine recommendations (updated as of 2025), note that while hypnotics provide modest short-term benefits, their long-term efficacy is limited, recommending cognitive behavioral therapy for insomnia (CBT-I) as first-line therapy.

Factors Affecting Efficacy

The efficacy of hypnotic medications can vary significantly based on patient-specific factors. In elderly individuals, age-related pharmacokinetic changes, such as reduced hepatic metabolism and glomerular filtration rate, lead to slower drug clearance and prolonged exposure, often resulting in diminished therapeutic efficacy and increased risk of adverse effects compared to younger adults. Comorbid conditions, particularly major depressive disorder, are associated with lower response rates to hypnotics; for instance, while eszopiclone may improve both sleep and depressive symptoms when combined with SSRIs, zolpidem extended-release primarily enhances sleep continuity without alleviating core depressive features, highlighting variable and often suboptimal outcomes in this population. Genetic variations, including polymorphisms in cytochrome P450 enzymes like CYP2C19 and CYP3A4, influence the metabolism of benzodiazepines and non-benzodiazepine hypnotics, thereby affecting drug duration, plasma levels, and overall clinical response, with poor metabolizers experiencing extended effects and ultra-rapid metabolizers showing reduced efficacy. Treatment-related variables further modulate hypnotic . Prolonged use beyond 2-4 weeks is linked to tolerance development, where initial improvements in sleep latency and duration wane, rendering long-term administration ineffective for chronic insomnia management. Optimal dosing timing, typically 30 minutes before to align with onset, maximizes subjective satisfaction and quality, as earlier administration may lead to dissatisfaction due to mismatched sleep-wake intervals. , common in older adults with multiple comorbidities, increases the risk of drug-drug interactions that alter hypnotic , potentially reducing through competitive metabolism or additive . Hypnotics demonstrate differential effectiveness depending on insomnia subtype. They are generally more effective for sleep-onset insomnia, with agents like and significantly reducing latency, whereas options for sleep-maintenance insomnia, such as or extended-release formulations, show moderate benefits but with greater variability in total sleep time improvements. Combining hypnotics with (CBT-I) enhances overall outcomes, including sustained sleep improvements and successful medication discontinuation, as supported by recent analyses emphasizing integrated approaches in clinical guidelines. Emerging research highlights gaps in personalized hypnotic therapy, particularly regarding (hypocretin) gene variants. Studies from 2025 indicate associations between polymorphisms in orexin-related genes (e.g., HCRTR1/2) and altered sleep-wake regulation, suggesting potential for tailored responses to antagonists like , though clinical translation remains limited by the need for larger validation trials.

Risks and Safety

Common Side Effects

Common side effects of hypnotic medications, particularly benzodiazepines and Z-drugs, often involve , manifesting as daytime drowsiness, , and impaired coordination. These effects, which may include low blood pressure, reduced heart rate, or exacerbated dizziness, particularly when combined with blood pressure medications, are reported in approximately 10-20% of users taking benzodiazepines, contributing to reduced alertness and psychomotor performance the following day. Effects can vary by drug type (e.g., zolpidem, benzodiazepines) and are more pronounced in elderly or long-term users; consultation with a healthcare provider is recommended to mitigate interaction risks. Cognitive impairments are also prevalent, with memory disturbances such as being especially common among short-acting agents like and . This form of amnesia, affecting the formation of new memories, occurs in 1-10% of users and is more pronounced with higher doses or in combination with other sedatives. Gastrointestinal adverse reactions include dry mouth and , which are frequently observed across hypnotic classes due to their properties. Antihistamine-based hypnotics, such as diphenhydramine, additionally cause through enhanced anticholinergic activity, affecting bowel motility. These side effects exhibit dose-dependent patterns and are more pronounced in vulnerable populations, such as the elderly, where they heighten the risk of falls due to compounded and coordination deficits. Meta-analyses indicate that use increases fall risk by 60-80% in older adults, underscoring the need for cautious dosing in this group.

Dependence, Tolerance, and Withdrawal

Tolerance to hypnotics, particularly those acting on GABA_A receptors such as benzodiazepines and non-benzodiazepine receptor agonists (Z-drugs), develops rapidly, often within 1-2 weeks of continuous use, due to neuroadaptive changes including downregulation and desensitization of receptor subunits. Chronic exposure leads to reduced receptor sensitivity, with specific alterations in α1, α2, and α5 subunits contributing to diminished sedative and hypnotic effects, necessitating higher doses to achieve the same therapeutic response. This tolerance is more pronounced for sleep-inducing properties than anxiolytic effects, limiting the long-term efficacy of these agents for management. Dependence on hypnotics encompasses both physical and psychological components, arising from prolonged use that reinforces reliance on the drug for sleep initiation and maintenance. Physical dependence manifests as rebound insomnia or heightened anxiety upon discontinuation, driven by the same GABA_A receptor adaptations that underlie tolerance. Approximately 15% of users develop long-term use (>1 year), which is associated with increased risk of dependence, particularly for benzodiazepine receptor agonists. Psychological dependence involves behavioral patterns where patients perceive the drug as indispensable, often exacerbated by underlying sleep disorders. Withdrawal from hypnotics can produce a of symptoms, ranging from mild autonomic hyperactivity to severe neurological effects, depending on the agent and duration of use. Common manifestations include anxiety, , tremors, and sweating, while barbiturates carry a higher risk of seizures and due to their broader impact on . typically involves gradual tapering to minimize symptom intensity, with recommended dose reductions of 10-25% per week under medical supervision, often supplemented by longer-acting benzodiazepines or supportive therapies for benzodiazepine-like hypnotics. Risk factors for developing tolerance, dependence, and severe withdrawal include high-dose regimens, extended treatment durations beyond 4-6 weeks, and with other depressants. Recent 2024 analyses of dual orexin receptor antagonists, such as and , indicate a substantially lower potential for these risks compared to traditional hypnotics, owing to their distinct mechanism of promoting suppression without receptor .

Overdose Risks

Overdose risks associated with hypnotics vary significantly by , primarily due to differences in their therapeutic indices and mechanisms of action. Barbiturates pose the highest , characterized by profound leading to and . In contrast, benzodiazepines and Z-drugs (non-benzodiazepine hypnotics such as , , and ) have a wider safety margin, making isolated overdoses rarely lethal, though they can cause significant and respiratory compromise when combined with other depressants. Orexin receptor antagonists, a newer class including and , exhibit low toxicity profiles even in overdose scenarios. Barbiturates have a narrow , with the ratio of lethal to effective dose typically ranging from 3:1 to 30:1, approximating around 10 times the therapeutic dose for many agents. Overdose manifests as severe respiratory depression, , , and progression to or apnea, often requiring . There is no specific ; management relies on supportive care, including airway protection, hemodynamic stabilization with fluids and vasopressors, and in severe cases, enhanced elimination via multiple-dose activated charcoal or for long-acting agents like . In-hospital mortality with aggressive supportive measures is low at 0.5–2%, but untreated cases carry high lethality due to the drug's potent suppression of vital functions. Benzodiazepines and Z-drugs are considerably safer in monotherapy overdose, with fatalities uncommon unless combined with opioids or alcohol, as their ceiling effect on respiratory depression limits progression to apnea. Symptoms include drowsiness, , and mild to moderate respiratory depression, but life-threatening complications are rare in isolation. , a competitive , can reverse effects in acute settings but carries risks, including seizures (occurring in up to 16% of high-risk patients, such as chronic users) and precipitation of withdrawal; it is thus reserved for select cases without contraindications like tricyclic antidepressant co-ingestion. Z-drugs share this profile, with overdose mortality estimated at one death per 900 cases, primarily managed supportively through monitoring and ventilation if needed. Orexin antagonists demonstrate minimal acute toxicity in overdose, with primary effects limited to excessive and no significant respiratory or cardiovascular depression reported even at supratherapeutic doses. No specific exists, and management is supportive, focusing on observation without need for intensive interventions in most instances. Clinical data indicate no major adverse outcomes or fatalities from isolated overdoses, underscoring their favorable safety margin compared to traditional hypnotics. Epidemiologically, hypnotic-related overdose deaths have declined sharply since the , attributable to the replacement of high-risk with safer alternatives like benzodiazepines and subsequent Z-drugs, reducing barbiturate poisonings to minimal levels by the late . However, mixed overdoses remain a concern, particularly with opioids; in 2023, approximately 14% of opioid-involved overdose deaths also included benzodiazepines, often exacerbating respiratory depression and contributing to polysubstance fatalities. Provisional data for 2024 indicate a further 27% decline in total deaths to approximately 80,400, the lowest since 2019.

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