GABAA receptor positive allosteric modulators Benzodiazepines Benzodiazepines can be useful for short-term treatment of insomnia. Their use beyond 2 to 4 weeks is not recommended due to the risk of dependence. It is preferred that benzodiazepines be taken intermittently and at the lowest effective dose. They improve sleep-related problems by shortening the time spent in bed before falling asleep, prolonging sleep time, and reducing wakefulness. 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. Some experts suggest using nonbenzodiazepines preferentially as a first-line long-term treatment of insomnia. 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.
Nonbenzodiazepines 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), 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 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 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 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.
GABAA receptor agonists The
GABAA receptor agonist gaboxadol (THIP; LU-2-030), a
synthetic derivative of the
neurotransmitter γ-aminobutyric acid (GABA) and an
analogue of the
alkaloid muscimol, underwent formal clinical development for the treatment of
insomnia and reached
phase 3 clinical trials for this indication in the 1990s and 2000s. It was found to effectively improve
sleep onset and
duration in people with
insomnia. 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.
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. 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.
GABAB receptor agonists The
GABAB receptor agonist sodium oxybate (SXB; Xyrem), also known as
γ-hydroxybutyrate (GHB), has hypnotic and sleep-improving effects. 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. This condition has very high rates of
non-restorative sleep (unrefreshing sleep) that may be directly involved in its symptoms. In addition, sodium oxybate was limitedly studied to improve
insomnia in people with
depression or
bipolar disorder. 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.
GABA reuptake inhibitors 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). 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 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 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 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-HT2A receptor antagonists Serotonin 5-HT2A receptor antagonists such as
ritanserin,
ketanserin,
eplivanserin,
volinanserin,
nelotanserin, and
pimavanserin have been studied and developed to improve sleep. They do not improve
sleep onset, but have been found to increase
slow wave sleep (deep sleep) and reduce
nighttime awakenings. They have been found to increase
slow wave sleep (deep sleep) in people with
insomnia and healthy individuals.
Cannabinoids 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.
Cannabidiol (CBD), which acts differently than other cannabinoids like THC, is not effective in improving sleep on the other hand. It is clinically effective for this purpose. 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. 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. 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.
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.
tricyclic antidepressants (TCAs) such as
amitriptyline,
doxepin, and
trimipramine, and
tetracyclic antidepressants (TeCAs) like
mirtazapine and
mianserin. 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. 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.
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==