This group of drugs is related tosedatives.Whereas the term sedative describes drugs that serve to calm orrelieve 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 fromanxiolysis toloss of consciousness), they are often referred to collectively assedative–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, bettersleep hygiene, the avoidance of caffeine andalcohol or other stimulating substances, or behavioral interventions such ascognitive 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 prescribednonbenzodiazepines (Z-drugs), while 10.8% are takingbenzodiazepines, as of 2010, in the USA.[11] Early classes of drugs, such asbarbiturates, 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 treatnight terrors orsleepwalking.[12] Elderly people are more sensitive to potential side effects of daytime fatigue andcognitive impairment, and ameta-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 asdependence 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 neurohormonemelatonin and its analogues (e.g.,ramelteon) serve a hypnotic function.[15]
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] Likealcohol, 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 disruptsleep architecture by decreasing sleep time, delaying time to REM sleep, and decreasing deepslow-wave sleep (the most restorative part of sleep for both energy and mood).[18][19][20]
Other drawbacks of hypnotics, including benzodiazepines, are possibletolerance 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 asnitrazepam anddiazepam, have residual effects that may persist into the next day and are, in general, not recommended.[16]
It is not clear whether the newernonbenzodiazepine (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 USAgency 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 UKNational 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 oftraffic collisions among driving patients, as well as falls and hip fracture for all older patients.[9][23]
Nonbenzodiazepines (Z-drugs) are a class ofpsychoactive drugs that are "benzodiazepine-like" in nature. Nonbenzodiazepinepharmacodynamics 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 includezopiclone (Imovane),eszopiclone (Lunesta),zaleplon (Sonata), andzolpidem (Ambien). Since the generic names of all drugs of this type start withZ, they are often referred to asZ-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 thattolerance to nonbenzodiazepines may be slower to develop than with benzodiazepines.[failed verification] A different team was more skeptical, finding little benefit over benzodiazepines.[29]
Quinazolinones are also a class of drugs that function as hypnotics/sedatives that contain a 4-quinazolinone core. Examples of quinazolinones includecloroqualone,diproqualone,etaqualone (Aolan, Athinazone, Ethinazone),mebroqualone,afloqualone (Arofuto),mecloqualone (Nubarene, Casfen), andmethaqualone (Quaalude). This class of drugs has been largely discontinued and is no longer used clinically.
The development of gaboxadol was discontinued in 2007.[47][48][49] This was due to high rates ofpsychiatric andhallucinogenic effects indrug 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 thepharmaceutical industry at the time owing to bizarre reports ofzolpidem (Ambien)-induceddelirium that emerged in the media in 2006, which may have made the developer of gaboxadol more concerned about potential liability issues.[47] According to journalistHamilton 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 byDavid Nutt and colleagues following the discontinuation of its development.[51][52]
Muscimol, the compound from which gaboxadol was derived, is anaturally occurring constituent ofAmanita mushrooms such asAmanita muscaria (fly agaric) and is apotent GABAA receptor agonist similarly.[53][54] However, muscimol is lessselective, moretoxic, and far less-researched than gaboxadol.[53][55][54][56] Muscimol is reported to inducesleep 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 andAmanita mushrooms for claimed therapeutic benefits, the most prominently cited of which is improved sleep, has become increasingly prominent.[53][59][60]
Sodium oxybate also completed formal clinical development forfibromyalgia.[5][66] This condition has very high rates ofnon-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 includingpain andfatigue.[5] However, despite its effectiveness, sodium oxybate was ultimately not approved for treatment of fibromyalgia owing mostly to concerns about possiblemisuse.[5] Sodium oxybate has also been investigated and been of interest to improve sleep and associated symptoms in other conditions with sleep disruption, such asmyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) andlong COVID, which also have high rates of non-restorative sleep.[4][69][67][70] In addition, sodium oxybate was limitedly studied to improveinsomnia in people withdepression orbipolar 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 adate-rape drug, although the actual prevalence of this appears to be much lower than popular perception.[72]
The GABAB receptor agonistbaclofen 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 acontrolled substance and has much less or nomisuse 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 longerelimination half-life andduration of action in comparison (half-life 3–4hours versus 0.5–1.0hours, respectively).[73][76][75]
Melatonin, the hormone produced in thepineal gland in the brain and secreted in dim light and darkness, among its other functions, promotes sleep indiurnal mammals.[80] It activates themelatoninMT1 andMT2 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]Syntheticanalogues of melatonin, ormelatonin receptor agonists, have also been made. Among these,ramelteon andtasimelteon are used for sleep disorders.Agomelatine is an antidepressant of this class, with some studies also reporting an effect on sleep.[83]
α2-Adrenergic receptoragonists likeclonidine 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 withattention deficit hyperactivity disorder (ADHD), for instance duestimulant therapy.[120][121][122] Similarly to clonidine, the α2-adrenergic receptor agonistdexmedetomidine has sedative and hypnotic effects and is used to producesedation in hospital settings.[123] The sleep induced by dexmedetomidine is said to closely resemble natural sleep.[123][124][125] Theselectiveα2A-adrenergic receptor agonisttasipimidine (ODM-105) is under development for the treatment of insomnia and is inphase 2clinical trials for this indication as of October 2024.[126][127] α2-Adrenergic receptor agonists can producehypotension andbradycardia asside 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 agonistguanfacine appears to show less sedation and hypotension than clonidine.[129]
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, whenchloral 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 inoverdose and tended to cause physical and psychological dependence.[164][165][166]
During the 1970s,quinazolinones[167] andbenzodiazepines 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 withalcohol or otherdepressants. Questions have been raised as to whether they disturb sleep architecture.[168]
Nonbenzodiazepines or Z-drugs likezolpidem 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 withoutlongitudinal studies. However, some psychiatrists recommend these drugs, citing research suggesting they are equally potent with less potential for abuse.[25]
^Because the drugs have a shorterelimination 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.
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^Benca RM (March 2005). "Diagnosis and treatment of chronic insomnia: a review".Psychiatric Services.56 (3):332–343.doi:10.1176/appi.ps.56.3.332.PMID15746509.Evidence for the utility of currently available nonbenzodiazepine hypnotics points to their primary efficacy as sleep-onset, rather than as sleep-maintenance, agents. Once again, longer-term randomized, double-blind, controlled studies that demonstrate the efficacy of these agents have not been performed, but safety over the longer term has been demonstrated in open-label studies, with minimal evidence of rebound phenomena. By comparison with benzodiazepines, there has been less evidence of subjective and objective next-day residual effects associated with zolpidem or subjective next-day impairment with zaleplon, even when the latter has been delivered in the middle of the night.
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^"Merck & Co and Lundbeck's sleep drug terminated in Phase III".PharmaTimes. 29 March 2007. Retrieved30 September 2025.The firms said they are discontinuing studies of the because data from recently-completed Phase III studies suggest that the overall clinical profile for gaboxadol in insomnia does not support further development. As a result of this new information, Merck and Lundbeck added that they will not file gaboxadol with the US Food and Drug Administration, or any other regulatory agencies worldwide, and are terminating the project.
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^abcJohnston GA (October 2014)."Muscimol as an ionotropic GABA receptor agonist"(PDF).Neurochem Res.39 (10):1942–1947.doi:10.1007/s11064-014-1245-y.PMID24473816.We now know that muscimol is a potent agonist at GABAA receptors, a potent partial agonist at GABAC receptors and inactive at GABAB receptors. Unlike bicuculline and TPMPA, it does not distinguish between GABAA and GABAC receptors. It is a weak inhibitor/substrate of GABA uptake and not a substrate for GABA transaminase [18–21].
^Frølund B, Ebert B, Kristiansen U, Liljefors T, Krogsgaard-Larsen P (August 2002). "GABA(A) receptor ligands and their therapeutic potentials".Curr Top Med Chem.2 (8):817–832.doi:10.2174/1568026023393525.PMID12171573.The fact that muscimol is a non-specific GABAA receptor agonist [38, 39], a substrate for the GABA-metabolizing enzyme, GABA transaminase [40], and moreover a neurotoxin, makes the compound therapeutically less valuable. [...] Further conformational restriction of the GABA structural element in muscimol has been achieved by incorporating the amino group into a piperidine ring leading to the bicyclic analogue, THIP, a specific GABAA agonist [11]. THIP has been shown to be devoid of the neurotoxic properties of muscimol and, in contrast to muscimol, is metabolically stable.
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