Nootropics

Aniracetam is a fat-soluble piracetam analog that positively modulates AMPA glutamate receptors. It was marketed in Italy and Japan for dementia and post-stroke cognitive symptoms, and placebo-controlled trials in Alzheimer-type dementia gave contradictory answers. It is no longer in clinical use, and in healthy animals it does nothing measurable.

Coluracetam, originally MKC-231, is the one racetam with a genuinely distinct mechanism: it enhances high-affinity choline uptake by acting on the choline transporter CHT1 itself. Everything known about it comes from rodents with chemically lesioned cholinergic neurons. No human trial with a published abstract is cited here.

Fasoracetam is a racetam repurposed as a metabotropic glutamate receptor activator and trialed in adolescents with ADHD who carry disruptive variants in mGluR network genes. A 30-patient open-label dose-escalation study with one single-blind placebo week reported significant improvement on global rating scales and good tolerability. That is a phase I result and the only human efficacy evidence there is.

Nefiracetam is a Japanese piracetam derivative that potentiates nicotinic α4β2 and NMDA receptors at nanomolar concentrations, through Gs proteins and protein kinase C. Its human testing went in an unexpected direction — post-stroke depression and apathy rather than memory — and the results were mixed at best: no overall antidepressant effect in 159 patients, a positive apathy signal in one trial and nothing in a second that could only randomize 13.

Noopept is a Russian dipeptide designed to mimic the piracetam pharmacophore, reported active at doses about a thousandth of piracetam's. It is a prodrug: the parent is undetectable in rat brain an hour after dosing, and the active species is cycloprolylglycine, a peptide the brain already makes. Its clinical evidence is Russian, small and uncontrolled, and its primary molecular action appears to be stabilization of HIF-1.

Oxiracetam is the 4-hydroxy analog of piracetam, prescribed for decades in Italy and South Korea for cognitive impairment. Small trials from the late 1980s and early 1990s reported benefit in mild dementia, but a 500-patient trial published in 2026 found no effect whatsoever on post-stroke cognition. South Korea's regulator recommended suspending prescriptions in January 2023.

Phenylpiracetam is a Soviet-era piracetam analog with a phenyl ring on the pyrrolidone, developed in 1983 and prescribed in Russia as Phenotropil. Modern work identifies the dopamine transporter as its only significant molecular target, and the two enantiomers do different things. It was the first nootropic banned in sport, in 1998. Its human evidence is substantial but almost entirely Russian and non-randomized: a matched 400-patient stroke-rehabilitation study, a 56-patient comparison against piracetam and a 1170-patient observational program.

Piracetam is the original "nootropic". C. Giurgea developed it in the late 1960s and coined the word to describe it. It is licensed in several countries for cognitive disorders, vertigo and cortical myoclonus. The evidence is mixed. An older meta-analysis found a global benefit in older adults with cognitive impairment, but a 2024 meta-analysis could not confirm an effect on memory.

Pramiracetam is a Parke-Davis piracetam derivative with a basic diisopropylaminoethyl side chain, far more potent than piracetam in animal amnesia models. Its two positive controlled human results are narrow: partial reversal of scopolamine-induced amnesia in healthy volunteers and improved delayed recall in young men with memory problems after head injury or anoxia. In Alzheimer's disease it did nothing.

Modafinil is a prescription wakefulness-promoting drug for narcolepsy, obstructive sleep apnea and shift work sleep disorder. It is widely used off-label as a "smart drug". In healthy people who are not sleep-deprived, a meta-analysis found only a small overall cognitive effect, driven mainly by memory updating.

ACD856 is an experimental oral drug from the Swedish company AlzeCure Pharma. It is a positive allosteric modulator of the Trk receptors: it does not replace BDNF or NGF but makes TrkA, TrkB and TrkC respond more strongly to them. In mice and rats it reversed drug-induced and age-related memory deficits and shortened immobility in the forced swim test. In people it has only been through phase 1: single doses up to 150 mg and seven days at up to 90 mg a day were well tolerated in healthy volunteers, it reached the cerebrospinal fluid, and it shifted the resting EEG, but no published trial has tested whether it improves memory or mood. Every published study comes from the developer.

9-Me-BC is a β-carboline — the same tryptophan-derived ring system found in cooked meat, coffee and tobacco smoke, and in human blood and brain. Most members of that family damage dopaminergic neurons, which is why they have been investigated as causes of Parkinson's disease; 9-Me-BC does the opposite in cell culture and in one rat study, raising tyrosine hydroxylase, inducing neurotrophic factors and restoring dopamine after a neurotoxin. Ten days of treatment also improved maze learning in rats and thickened dendrites in the dentate gyrus. No human has been studied at any dose.

Adderall contains mixed amphetamine salts, with approximately a 3:1 dextro- to levo-amphetamine ratio. Immediate-release tablets and Adderall XR deliver the same mixture at different rates. Controlled trials support ADHD symptom reduction; this is treatment evidence, not proof of general cognitive enhancement.

ASP4345 is an experimental oral drug from Astellas, a positive allosteric modulator of the dopamine D1 receptor: it does not switch the receptor on, but makes it respond to lower concentrations of dopamine. It was developed for the cognitive impairment of schizophrenia. Phase 1 found once-daily pharmacokinetics, entry into the cerebrospinal fluid and, in 48 patients over 14 days, faster reaction times than placebo on two computerized tests. The phase 2 trial then failed: in 233 patients, 50 or 150 mg a day for 12 weeks did no better than placebo on a standard cognitive battery or on a test of everyday functioning, and development was stopped. Those results are posted on the trial registry, which lists no journal publication of them.

BPAP ((−)-1-(benzofuran-2-yl)-2-propylaminopentane) is a research compound made by Joseph Knoll's Budapest group and Fujimoto Pharmaceutical by swapping the phenyl ring of PPAP for a benzofuran, and chosen from 65 analogs as a possible successor to selegiline. In rat tissue it raised the release of dopamine, norepinephrine and serotonin evoked by nerve impulses at femtomolar to picomolar concentrations, without releasing them at rest, and in the shuttle box it was about 130 times as potent as selegiline. It also blocks dopamine and norepinephrine reuptake more potently than cocaine. No human has been studied at any dose, a 2016 longevity benefit in rats was not reproduced in a 2024 study of aged rats, and almost all of the work comes from the inventors and their industrial partner.

Bromantane is a lipophilic adamantane stimulant-anxiolytic developed in the Soviet Union and marketed in Russia as Ladasten for asthenic disorders. A 30-person, single-blind placebo trial reported faster and greater symptom relief, while a 728-patient uncontrolled program reported improvement from day 3; neither result has been independently replicated. Its best-supported mechanism is not direct receptor agonism or dopamine transporter blockade, but altered expression of dopamine-synthesis enzymes in animals.

Clonidine is a central alpha-2 adrenergic agonist that lowers sympathetic activity and blood pressure. Its extended-release tablets are also used for ADHD, alone or alongside a stimulant. Pediatric trials support symptom improvement, with sedation, fatigue and slower heart rate as important tradeoffs.

Concerta is an osmotic extended-release formulation of methylphenidate hydrochloride for ADHD. A controlled pediatric comparison found effects lasting through 12 hours and broadly matching immediate-release methylphenidate given three times daily. It is the same active drug as Ritalin, with a different delivery system.

DL-phenylalanine (DLPA) is a 50:50 mix of the dietary amino acid L-phenylalanine and its mirror image, D-phenylalanine. It is sold for mood and pain on the strength of two 1970s–80s ideas: that L-phenylalanine feeds catecholamine and phenylethylamine synthesis, and that D-phenylalanine slows the breakdown of enkephalins. The human evidence is old and thin. Small German depression studies were positive but had no placebo arm, and the only placebo-controlled chronic-pain trial of D-phenylalanine found no analgesic effect. The strongest modern data concern L-phenylalanine alone: short-term tolerability up to 12 g/day in healthy men and gut-hormone effects at 10 g.

Doxepin is a tricyclic antidepressant first approved in the United States in 1969 that is now also licensed there, at 3 and 6 mg, for insomnia marked by trouble staying asleep: doses 10 to 100 times lower than antidepressant ones. At those doses it acts almost only as a histamine H1 blocker. In industry-funded trials of up to 12 weeks it cut time awake during the night by about 22–23 minutes, with little effect on how quickly people fell asleep, and the American Academy of Sleep Medicine gives it a weak recommendation for sleep maintenance on evidence it rates as very low quality. At 75–300 mg a day it is a sedating antidepressant with the anticholinergic side effects and overdose toxicity of its class.

Guanfacine is a selective alpha-2A adrenergic agonist, first used to lower blood pressure, whose extended-release form (Intuniv) is approved for ADHD in children and adolescents, alone or added to a stimulant; Japan approved it for adults in 2019. In pediatric trials it reduced ADHD symptoms by a moderate amount, at the cost of sleepiness and lower blood pressure and pulse. Its reputation as a cognitive enhancer comes from monkey studies showing that it strengthens prefrontal working-memory circuits, but it did not improve memory or executive function in healthy young men or in healthy adults over 75.

KW-6356 (sipagladenant) is a selective blocker and inverse agonist of the adenosine A2A receptor, made by Kyowa Kirin, the company behind istradefylline, for Parkinson's disease. In a 12-week trial in 168 people with early, untreated Parkinson's disease, motor scores improved more than on placebo, but the difference was about 2 points and its confidence interval crossed zero; a 503-patient trial as an add-on to levodopa met its primary endpoint, and has been reported only as a conference abstract. Insomnia was the commonest side effect in healthy volunteers. Kyowa Kirin stopped developing it in 2022.

L-THP (levo-tetrahydropalmatine, or rotundine) is a tetrahydroprotoberberine alkaloid used in China as a sedative and analgesic and investigated for substance-use disorders. One 120-person pilot trial reported less heroin craving and more abstinence, but treatment caused markedly more early dropout. A small phase-I study found 30 mg twice daily tolerable for 3.5 days, not proof of long-term efficacy or safety.

L-tyrosine is a dietary amino acid and catecholamine precursor, not a reliably demonstrated everyday nootropic. Small crossover trials suggest that large acute doses can preserve selected attention, working-memory or psychomotor outcomes during sleep loss, cold, noise or demanding multitasking, but reviews judge the evidence heterogeneous and too weak for a firm recommendation. Results in unstressed adults are mixed and baseline-dependent. A meta-analysis found no endurance benefit, although one later 12-person cycling experiment was positive. Four weeks at up to 4 g/day produced no dose-related safety signal in 30 healthy men, but that does not establish long-term or clinical-population safety.

N-acetyl-L-tyrosine (NALT) is a water-soluble acetylated derivative of L-tyrosine. Human evidence is almost entirely intravenous nutrition research, where 35–60% was recovered unchanged in urine and plasma tyrosine often did not rise. There are no cited human oral trials showing that NALT improves cognition, stress performance or energy.

PPAP (1-phenyl-2-propylaminopentane) is a research stimulant made in Joseph Knoll's Budapest laboratory as a version of selegiline with the MAO-B inhibition taken out. In rats it improved learning and retention, reversed the learning deficit caused by tetrabenazine and was active in the forced swimming test, without releasing catecholamines the way amphetamine does. No human has been studied at any dose: its inventor wrote in 2001 that, despite his group's efforts, it had never been tested clinically, and almost every experiment comes from the group that invented it.

Ritalin tablets contain immediate-release methylphenidate hydrochloride, a prescription stimulant used for ADHD and narcolepsy. ADHD efficacy is well supported, while its shorter delivery profile means that trial regimens often use multiple daily doses. This page focuses on ordinary tablets, not the separate Ritalin LA formulation.

Selegiline (L-deprenyl) is an irreversible MAO-B inhibitor created in Joseph Knoll's Budapest laboratory in the 1960s and prescribed for Parkinson's disease and, as a skin patch, for major depression. In early Parkinson's disease 10 mg a day delayed the need for levodopa by about nine months, though whether that was protection or symptom relief was never settled; the patch beat placebo modestly in adult depression and not at all in adolescents. It is broken down to l-methamphetamine and l-amphetamine. Its reputation as an anti-aging drug rests on rat longevity studies that replicated inconsistently, and a Cochrane review found no clinically meaningful benefit in Alzheimer's disease.

Trazodone is an antidepressant licensed for major depression in adults that is now prescribed in the United States mainly at low doses as an off-label sleep aid. It blocks 5-HT2A serotonin and alpha-1 adrenergic receptors strongly and the serotonin transporter weakly. Across 44 randomized trials it improved sleep quality and cut night-time awakenings without lengthening how long people felt they slept, at the cost of more side effects, and the American Academy of Sleep Medicine advises against it for chronic insomnia. In depression it beat placebo but ranks among the less effective and less well tolerated antidepressants.

Vyvanse is lisdexamfetamine dimesylate, a prodrug converted in blood to dextroamphetamine. It has established ADHD efficacy and a separate US indication for moderate-to-severe binge-eating disorder in adults. Its prodrug design changes delivery but does not remove stimulant adverse effects or misuse potential.

AF710B, now developed by Anavex Life Sciences as ANAVEX3-71, is an experimental drug that acts on two targets at once: it activates the M1 muscarinic acetylcholine receptor from an allosteric site, amplifying acetylcholine's own effect, and it is a sigma-1 receptor agonist. In Alzheimer's-model mice and rats, doses of 10 µg/kg a day improved memory and reduced amyloid, tau phosphorylation and glial inflammation, and in rats the benefits outlasted the end of treatment by weeks. In people it has been through a single-dose phase 1 study and a 71-person phase 2 trial in schizophrenia that met its safety endpoint but released no symptom or cognition results.

Alpha-GPC (choline alfoscerate) is a choline-containing phospholipid breakdown product, sold as a prescription drug in some countries and a supplement elsewhere. It is a precursor of both choline and acetylcholine. Its record is unusually mixed. One very large Korean cohort linked it to lower dementia conversion, while another linked it to higher 10-year stroke risk.

Citicoline (CDP-choline) is an intermediate in the synthesis of phosphatidylcholine, the main phospholipid in cell membranes. It is a prescription drug in some countries and a supplement in others. A meta-analysis found it improved cognitive status in mild cognitive impairment, Alzheimer's disease and post-stroke dementia, though the underlying studies were of poor quality.

Tropisetron is a prescription 5-HT3 receptor antagonist used as an antiemetic and a partial agonist at α7 nicotinic acetylcholine receptors. Small adjunctive trials in schizophrenia reported better auditory P50 sensory gating and selected attention or memory measures after 1 day to 8 weeks, usually in nonsmokers taking risperidone. Those studies do not establish it as a general cognitive enhancer.

Uridine monophosphate (UMP) is a nucleotide and dietary source of uridine, one of the precursors used to make phosphatidylcholine and other neuronal membrane phospholipids. In rodents, UMP raises brain phosphatides and can increase striatal acetylcholine release; after six weeks it also increased potassium-evoked, but not basal, striatal dopamine release in aged rats. Human cognitive evidence does not isolate UMP: the trials used it inside a multinutrient drink with choline, DHA, EPA, phospholipids, vitamins and selenium, and the primary cognitive outcomes were mixed.

BPN14770, now named zatolmilast, is an oral drug candidate from Tetra Therapeutics, a Shionogi subsidiary. It is an allosteric inhibitor of phosphodiesterase-4D (PDE4D), built to raise cAMP signaling in neurons without the vomiting that has stalled other PDE4 inhibitors. In mice carrying the human form of the enzyme it improved memory at oral doses of 0.01–0.03 mg/kg, and a 30-man crossover trial in fragile X syndrome reported gains in language-related cognition. The larger trials have not confirmed it. A 255-patient phase 2 trial in early Alzheimer's disease found no difference from placebo, and in May 2026 Shionogi reported that both phase 3 trials in fragile X syndrome had missed their primary endpoints.

Intranasal insulin is ordinary human insulin sprayed high into the nose so that some of it travels into the brain, where insulin receptors are dense in memory regions, while blood insulin and glucose barely change. Small trials found better memory in healthy adults and in people with mild cognitive impairment or Alzheimer's, but the largest trial, a 12-month phase 2/3 study in 289 people, found no benefit. Several trials in older surgical patients reported less delirium after surgery.

J147 is a synthetic small molecule from the Salk Institute. It descends from curcumin through a series of hybrid compounds and was chosen because it protected neurons in six different cell models of brain aging. Fed to mice, it improved memory in normal animals, in Alzheimer's-model mice treated late in the disease and in rapidly aging SAMP8 mice. Its target turned out to be the mitochondrial ATP synthase, which it partly inhibits, switching on AMPK. A phase 1 trial in healthy volunteers finished in 2020 and has never reported results, so there is no published human data at any dose.

NSI-189 is an investigational benzylpiperazine-aminopyridine selected for neurogenic activity rather than for a known receptor target. A 24-person phase 1b study produced exploratory mood and self-rated cognitive signals, but the 220-person phase 2 trial missed its primary depression endpoint at both 40 and 80 mg a day; some self-rated and CogScreen measures favored 40 mg, while Cogstate did not. Its strongest mechanistic findings remain in cell and rat injury models.

TAK-653 (osavampator, NBI-1065845) is an AMPA receptor positive allosteric modulator designed to amplify glutamate signaling only where glutamate is already being released — it binds the receptor's ligand-binding domain in a glutamate-dependent way and has virtually no agonist activity of its own, which in rats bought a 419-fold exposure margin against convulsions. In 24 healthy volunteers a single 6 mg dose raised motor-cortex excitability on TMS and produced a mild psychostimulant profile without euphoria or subjective drug effects. A phase 2 trial in depression reported a positive MADRS result, but only in a company press release; two phase 3 trials began in 2025.

Acetyl-L-carnitine (ALCAR) is the acetyl ester of L-carnitine and the body's main carnitine ester. It is sold as a supplement and, in some countries, as a prescription drug. Meta-analyses find that it eases depressive symptoms, mostly in older adults and across small, inconsistent trials, and that it reduces diabetic nerve pain at doses above 1.5 g a day, on very low-certainty evidence. It did not slow Alzheimer's disease in two year-long trials, and it made chemotherapy nerve damage worse in a large one.

Ashwagandha (Withania somnifera) extracts have modest human trial evidence for perceived stress and sleep, although pooled results differ by outcome and trial quality is mixed. KSM-66, a root-only extract standardized to at least 5% withanolides, is used in several well-known trials. Extract names and standardization measures matter: their trial results are not automatically interchangeable.

Aticaprant is an oral, short-acting antagonist of the kappa-opioid receptor, the receptor for dynorphin, developed for anhedonia and depression. In an 8-week trial in people with anhedonia it raised reward-related activity in the ventral striatum and modestly lowered anhedonia scores, and added to an SSRI or SNRI it lowered depression scores by 2–3 points more than placebo in a 6-week phase 2 trial. Johnson & Johnson then stopped its phase 3 program in March 2025 for insufficient efficacy, without publishing the data.

Bacopa monnieri is an Ayurvedic herb used traditionally to support memory. Randomized trials in healthy older adults found better verbal learning and delayed recall after about 12 weeks. A meta-analysis of nine trials found faster attention (Trail B) and choice reaction time. It is slow to act and commonly causes gut side effects.

Caffeine is the world's most widely used psychoactive compound, a methylxanthine that works by blocking adenosine receptors. At low to moderate doses it reliably improves alertness, vigilance, attention and reaction time, with weaker and less consistent effects on memory and higher-order judgment. It is the reference point every other stimulant on this wiki gets compared to.

Daridorexant (Quviviq) is a dual orexin receptor antagonist from Idorsia, approved for adult insomnia in the United States and the European Union in 2022. With a half-life of about 8 hours it is the shortest-acting of the three licensed orexin antagonists. In two 3-month phase 3 trials in 1,854 adults, 50 mg cut time awake during the night by 18–23 minutes and time to fall asleep by about 11 minutes compared with placebo, and improved self-rated daytime sleepiness; 25 mg did less and 10 mg had no effect on measured sleep. Benefits held over a further 9 months with no withdrawal or rebound insomnia.

Indolepropionamide (IPAM) is the amide of indole-3-propionic acid, a small indole related in structure to melatonin. Its inventors made it to get an antioxidant indole into the brain more easily, then reported finding a matching trace compound in rat brain. In their one published study it protected isolated rodent brain mitochondria at 10 nM and more than tripled the lifespan of a rotifer. That 2010 paper and the same authors' abandoned patent application are the whole evidence base: no other laboratory has published an experiment with IPAM, and it has never been tested in a mammalian disease model or in people.

ISRIB is an experimental small molecule that activates eIF2B, a protein-synthesis regulator, and counters part of the integrated stress response. Short courses improved memory in aged and brain-injured mice, sometimes weeks after treatment ended, but Alzheimer's-model results are mixed. A 2025 review found no published human trials of ISRIB; self-reported use does not establish a clinical benefit or a safe dose.

L-theanine is an amino acid found almost only in tea. Taken at 200 to 400 mg a day, it may reduce stress and anxiety in people under stressful conditions. Its best-known use is alongside caffeine, where the pair improves attention switching more than either alone. A 2025 meta-analysis found small improvements in subjective sleep.

Lemborexant (Dayvigo) is a dual orexin receptor antagonist from Eisai, approved for adult insomnia in the United States in 2019 and in Japan, Canada, Australia and several Asian countries. In older adults it shortened the time to fall asleep and cut night-time waking more than both placebo and extended-release zolpidem, and in a 12-month trial its benefits over placebo at 6 months were still present at a year. It had the largest effect on falling asleep of the three licensed orexin antagonists in a 2025 network meta-analysis; the price is a long half-life of 17–19 hours and dose-related somnolence, most of all at 10 mg.

Low-dose naltrexone (LDN) is naltrexone, an opioid receptor antagonist licensed at 50 mg a day for alcohol and opioid dependence, taken off-label at about 1–5 mg a day for fibromyalgia, Crohn's disease, multiple sclerosis and other chronic conditions. At 2–5 mg it blocks roughly a quarter to a half of the brain's mu-opioid receptors, and it is proposed to calm inflammatory glial cells as well. Small early trials were positive, but the larger placebo-controlled trials in fibromyalgia and Crohn's disease were negative, and long COVID has no published randomized trial.

Memantine is a prescription adamantane derivative that blocks pathologically active NMDA receptor channels with moderate affinity and fast on-off kinetics. A Cochrane review of 44 trials found small but consistent benefits in cognition, daily function, global status and behavior in moderate-to-severe Alzheimer's disease, with or without a cholinesterase inhibitor; it found no benefit in mild Alzheimer's disease. It slows deterioration rather than restoring lost cognition.

Paraxanthine (1,7-dimethylxanthine) is what most caffeine turns into in the body: about 80% of a caffeine dose is converted to it. Like caffeine it blocks adenosine receptors, and at 4 mg/kg it raised diastolic blood pressure and adrenaline in people about as much as the same dose of caffeine. It is now sold on its own as a supplement. Small crossover trials funded by the ingredient's sponsor report better scores on some attention, memory and reaction-time tests after 50 to 200 mg, though their main statistical tests were not significant.

PRL-8-53 is a synthetic benzoic acid ester built on a phenethylamine skeleton, with one published human experiment: a double-blind, placebo-controlled test of a single 5 mg oral dose in 47 healthy adults. Recall of a 12-word list a day later rose from 5.16 to 7.37 words in order, with a smaller effect on learning the list and none on visual reaction time or hand steadiness. The result has never been replicated, and the paper's statistics and drug lot both have problems.

Rhodiola rosea is an Arctic and alpine herb marketed as an adaptogen for stress and fatigue. Some randomized trials report less mental fatigue, but one found it made fatigue worse. Systematic reviews describe the evidence as contradictory and the trials as poorly reported.

Sabroxy is a branded bark extract of Oroxylum indicum, the Indian trumpet tree. It is standardized to three flavones: oroxylin A, chrysin and baicalein. One 12-week randomized trial in older adults with memory complaints found better episodic memory than placebo. The same trial found no difference on most individual tests, the MoCA or self-rated cognition. That trial is the only controlled human study of the plant.

Saffron is the dried stigma of Crocus sativus; supplements usually contain extracts with several constituents rather than a single molecule. Human trials suggest benefits for mood and subjective sleep quality, but a 2026 meta-analysis found improvements on self-rated depression and anxiety scales without significant effects on Hamilton depression or anxiety ratings or overall mood scores. Results depend on the preparation and outcome measured. Trials of the branded extract affron mostly report modest gains on self-rated depression scores, but a 2021 EFSA review judged its mood evidence insufficient for a health claim.

Seltorexant (JNJ-42847922, MIN-202) is an investigational selective orexin-2 receptor antagonist from Janssen, developed with Minerva Neurosciences as an add-on treatment for major depression with insomnia symptoms. Unlike the licensed dual orexin antagonists it binds the OX2 receptor about 100 times more tightly than OX1, and its half-life is only 2–3 hours. Added to an antidepressant, 20 mg at bedtime lowered depression scores by about 3 points more than placebo in a phase 2 trial, mostly in people with marked insomnia, and a 586-patient phase 3 trial reported a 2.6-point advantage; a head-to-head phase 3 trial against quetiapine missed its primary endpoint, and as of mid-2026 it was not approved anywhere.

Suvorexant (Belsomra) was the first orexin receptor antagonist licensed for insomnia, approved in the United States in 2014. Instead of damping the whole brain through GABA-A receptors, as benzodiazepines and Z-drugs do, it blocks both receptors for orexin, the hypothalamic peptide that keeps people awake. At the licensed 15–20 mg doses, people in two 3-month trials reported 11–22 more minutes of sleep a night than on placebo, and polysomnography measured 17–31 fewer minutes awake after falling asleep, with smaller and less consistent effects on how quickly they fell asleep. Next-day sleepiness is its main drawback, and it is a Schedule IV controlled substance in the United States.