Hypnotic

Types

GABA_A receptor positive allosteric modulators

Main article: GABAA receptor positive allosteric modulator

Benzodiazepines

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. 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).

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. 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. Longer-acting benzodiazepines, such as nitrazepam and diazepam, have residual effects that may persist into the next day and are, in general, not recommended.

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. 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. Some experts suggest using nonbenzodiazepines preferentially as a first-line long-term treatment of insomnia. 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.

Older adults should not use benzodiazepines to treat insomnia unless other treatments have failed to be effective., which cites

• 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.

Their mechanism of action is primarily at GABAA receptors.

Nonbenzodiazepines

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.

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.

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),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. as next-day impairments were minimal. 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.

Barbiturates

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. Barbiturates are derivatives of barbituric acid. Examples include amobarbital, pentobarbital, phenobarbital, secobarbital, and sodium thiopental.

Quinazolinones

Main article: Quinazolinone, 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: Neurosteroid

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

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.

GABA_A receptor agonists

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. It was found to effectively improve sleep onset and duration in people with insomnia. In addition, and unlike other hypnotics like benzodiazepines, gaboxadol improved slow wave sleep, preserved sleep architecture, and did not suppress REM sleep. Moreover, in contrast to benzodiazepines, tolerance did not appear to develop to gaboxadol's hypnotic effects.

The development of gaboxadol was discontinued in 2007. 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. 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. 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. There has been some further study of gaboxadol as a hypnotic by David Nutt and colleagues following the discontinuation of its development.

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. However, muscimol is less selective, more toxic, and far less-researched than gaboxadol. Muscimol is reported to induce sleep in humans in addition to its well-known hallucinogenic effects that occur at sufficiently high doses. The drug shows similar effects on sleep in rodents as gaboxadol. 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.

GABA_B receptor agonists

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

Sodium oxybate also completed formal clinical development for fibromyalgia. This condition has very high rates of non-restorative sleep (unrefreshing sleep) that may be directly involved in its symptoms. Sodium oxybate improved sleep in fibromyalgia and showed moderate effectiveness in treating multiple symptoms across the condition including pain and fatigue. However, despite its effectiveness, sodium oxybate was ultimately not approved for treatment of fibromyalgia owing mostly to concerns about possible misuse. 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. In addition, sodium oxybate was limitedly studied to improve insomnia in people with depression or bipolar disorder. However, it was reported to paradoxically disrupt sleep and induce narcolepsy-like changes in these individuals. Moreover, concerns about misuse have limited use of sodium oxybate for other medical conditions. 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.

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. However, in people with narcolepsy, baclofen and sodium oxybate both improved sleep but only sodium oxybate reduced daytime sleepiness. In any case, research in this area is limited, and there remains significant interest in baclofen in the potential treatment of sleeping problems. Unlike sodium oxybate, baclofen is not a controlled substance and has much less or no misuse potential. Baclofen and sodium oxybate have been found to activate the GABAB receptor differently, which is thought to underlie the differences in their effects. 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 3–4hours versus 0.5–1.0hours, respectively).

GABA reuptake inhibitors

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. It has also been used off-label in the treatment of anxiety disorders and other conditions. 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). In addition, tiagabine has been reported to make sleep feel more restorative and to improve some cognitive outcomes. The drug has an elimination half-life of 5 to 8hours. While tiagabine may have hypnotic effects, off-label use is discouraged as it has been associated with new-onset seizures in people without epilepsy.

Melatonin receptor agonists

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

Histamine H₁ receptor antagonists

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. 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. Many sedating antihistamines also have anticholinergic activity that can produce side effects like cognitive impairment. Low-dose doxepin (Silenor) is approved by the FDA for the treatment of insomnia. 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. 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.

Orexin receptor antagonists

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. 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.

Serotonin 5-HT_2A receptor antagonists

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

Gabapentinoids

Main article: Gabapentinoid

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

Cannabinoids

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

α₁- and β-adrenergic receptor antagonists

Main article: Alpha-1 blocker, 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). It is clinically effective for this purpose. However, the drug is also an antihypertensive agent and can lower blood pressure, thereby producing side effects like dizziness and orthostatic hypotension. Certain non-selective hypnotics such as trazodone and tricyclic antidepressants (TCAs) like amitriptyline and trimipramine are also α1-adrenergic receptor antagonists. 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. Conversely, timolol alone produced no such effects. 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. 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. However, these two beta blockers have also been associated with insomnia similarly to selective beta blockers.

α₂-Adrenergic receptor agonists

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

Serotonin precursors

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

Multiple mechanisms

Antidepressants

Some antidepressants have hypnotic and/or sedative effects. These include the serotonin antagonist and reuptake inhibitor (SARI) trazodone, tricyclic antidepressants (TCAs) such as amitriptyline, doxepin, and trimipramine, and tetracyclic antidepressants (TeCAs) like mirtazapine and mianserin. 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. 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.

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. However, the most commonly used agents for insomnia are quetiapine and olanzapine. 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. 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. 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, 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.

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.

Other drugs

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

Comparative effectiveness

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

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. 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). 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.

History

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.

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. Barbiturates emerged as the first class of drugs in the early 1900s, 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.

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

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.

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.

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

Notes

References

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