Lemborexant

Lemborexant (E2006) is a dual orexin receptor antagonist (DORA) developed by Eisai [2]. It was approved in the United States in 2019 for adult insomnia with difficulty falling asleep, staying asleep or both [1], and is also approved in Japan, Canada, Australia and several Asian countries [3].

Trials in insomnia. A Bayesian adaptive phase 2 trial in 291 adults tested 1–25 mg for 15 nights; doses of 5 mg and above improved sleep efficiency and sleep onset on polysomnography and diaries at the start and end of treatment, while objectively measured waking during the night improved only at the higher doses [7]. SUNRISE 1 randomized 1,006 women aged 55 and over and men aged 65 and over with sleep-maintenance insomnia to 5 mg, 10 mg, extended-release zolpidem 6.25 mg or placebo for a month [2]. At the end, latency to persistent sleep was 23–28% shorter than on placebo and 37–41% shorter than on zolpidem; sleep efficiency rose 7–8 percentage points and wake after sleep onset fell 24–25 minutes more than on placebo, and 8–9 minutes more than on zolpidem, mostly in the second half of the night [2]. SUNRISE 2 randomized 971 adults to 5 mg, 10 mg or placebo for 6 months [4]. By sleep diary at month 6, time to fall asleep was about 27–30% shorter than on placebo, total sleep 19–23 minutes longer and wake after sleep onset 13–17 minutes shorter, and about 30% of people on lemborexant met the trial's definition of a sleep-onset responder against 18% on placebo [4]. These benefits were maintained in people who continued treatment to 12 months, with no rebound insomnia or withdrawal after stopping [5].

How it compares. In a 2025 network meta-analysis of eight trials, 10 mg had the largest effect of any licensed DORA dose on self-reported time to fall asleep (standardized mean difference −0.43), better than suvorexant and daridorexant 25 mg on that measure, and 10 mg also beat 5 mg on total sleep [6]; in an earlier network meta-analysis of week-1 outcomes, 10 mg had the largest effect against placebo on every primary outcome [8]. The 2022 Lancet network meta-analysis of 154 trials found lemborexant and eszopiclone the only drugs that beat placebo in long-term use (lemborexant standardized mean difference 0.41, very low certainty) and judged lemborexant's profile favorable, while calling its safety data inconclusive [9].

Older adults and dementia. SUNRISE 1 was run entirely in adults aged 55 and over [2]. In a 2026 meta-analysis of DORAs in people aged 65 and over, lemborexant and suvorexant caused more treatment-emergent adverse events than placebo, though not more serious ones [10]. In a small phase 2 trial in 62 people with Alzheimer's dementia and an irregular sleep–wake rhythm, some doses reduced night-time restlessness, sharpened the day–night difference in activity and shortened daytime sleep bouts, with no worsening of cognition, but each dose arm had only about 12 people [11]. A 2025 meta-analysis pooling lemborexant, suvorexant and ramelteon found fewer cases of delirium in hospitalized patients, on low-certainty evidence [12].

Midlife women. In the 280 women aged 40–58 in SUNRISE 2, the age range of the menopausal transition, lemborexant improved self-reported sleep through 12 months [13].

Orexin and wakefulness. Orexin neurons in the lateral hypothalamus fire during wakefulness and fall silent in sleep, and losing them causes narcolepsy [14][15]. Blocking their two receptors lowers the wake drive rather than sedating the brain through GABA-A receptors [16].

Binding. Lemborexant is a competitive antagonist at both orexin receptors, with IC50 values of 6.1 nM at OX1 and 2.6 nM at OX2 [1]. It binds and dissociates quickly, is equally potent at human, rat and mouse receptors, is selective over 88 other targets, and in computer models sits in the receptor pocket in the same folded "horseshoe" shape as suvorexant [17]. Its main metabolite, M10, binds the receptors about as well as the parent drug [1].

In animals. Oral lemborexant blocked the orexin-induced rise in the stress hormone ACTH in rats and promoted sleep in mice and rats; it increased REM and non-REM sleep in proportion, whereas zolpidem reduced REM sleep [18]. It had no sleep-promoting effect in mice lacking orexin neurons, showing that it works through orexin signaling; repeated dosing did not reduce its effect, and it did not deepen ethanol anesthesia or impair motor coordination [18]. Mice given 10 or 30 mg/kg showed cataplexy-like behavior when offered chocolate, a trigger for cataplexy in narcoleptic mice [1].

Circadian rest–activity. In Alzheimer's dementia with an irregular sleep–wake rhythm, actigraphy suggested less night-time activity and more consolidated daytime wakefulness on some doses [11].

Tablets and food. Lemborexant comes as 5 and 10 mg film-coated tablets [1]. A high-fat meal lowers the peak level by 23%, raises total exposure by 18% and delays the peak by 2 hours [1].

A long tail. Its effective half-life is 17–19 hours, and 9 hours after a 10 mg dose about a quarter of the peak level remains [19]. Even so, phase 1 studies found no clinically relevant next-morning effects on sleepiness, coding speed or vigilance at doses up to 10 mg [19].

Special groups. In mild liver impairment the peak rose 58% and total exposure 25%; in moderate impairment the peak rose 22% and total exposure 54%, so the dose there is capped at 5 mg [20]. Severe kidney impairment raised total exposure about 1.5-fold without a dose change [21]. Age, sex, race and body mass index made no clinically relevant difference [1].

Common effects. In the first 30 days of the phase 3 trials, somnolence or fatigue affected 6.9% on 5 mg and 9.6% on 10 mg against 1.3% on placebo, headache 5.9% and 4.5% against 3.4%, and nightmares or abnormal dreams 2.2% on 10 mg [1]. Over 6 months in SUNRISE 2, somnolence affected 8.6% on 5 mg and 13.1% on 10 mg against 1.6% on placebo, and 8.3% on 10 mg stopped because of side effects against 4.1% on 5 mg and 3.8% on placebo [4]. In SUNRISE 1, adverse events were reported by 28–31% on lemborexant, 35% on zolpidem and 25% on placebo [2]. Somnolence on 10 mg was more frequent in people aged 65 and over: 9.8% against 7.7% in the first month [1], and 19.0% against 10.9% over 6 months in SUNRISE 2 [4].

Narcolepsy-like effects. Sleep paralysis occurred in 1.3% on 5 mg and 1.6% on 10 mg, and hypnagogic hallucinations in 0.1% and 0.7%, with none on placebo; two complex sleep behavior events occurred, both on 10 mg [1]. No events were judged to be cataplexy in SUNRISE 1 or SUNRISE 2 [2][4]. Sleep paralysis was its strongest signal in US adverse-event reports [27].

At night and the next day. When healthy older adults were woken 4 hours after a dose, both doses increased body sway compared with placebo, although less than zolpidem did; neither changed how loud a sound was needed to wake them, and 10 mg worsened attention and memory, but by morning there were no residual effects on balance or cognition [26]. In on-road driving tests 9 hours after bedtime doses of up to 10 mg, average performance was not impaired [25], although the label notes impairment in some individuals on 10 mg [1]. Falls were no more frequent than on placebo over 6 months in SUNRISE 2 (1.6% against 3.1%) [4].

Alcohol. A single 10 mg dose taken with alcohol worsened attention and memory more than alcohol alone, and alcohol raised lemborexant's total exposure by 70% and its peak by 35% [28].

Breathing. Over 8 nights at 10 mg, the apnea–hypopnea index did not change in mild sleep apnea [22] or in moderate-to-severe sleep apnea [23], and overnight oxygen saturation did not fall in moderate-to-severe COPD [24]. The label still advises weighing respiratory effects, because these studies were short [1].

Mood. Suicidal ideation or behavior on questionnaires was slightly more frequent on lemborexant (0.3–0.4%) than placebo (0.2%) [1]; in US adverse-event reports, DORAs were not linked to more suicidality than trazodone [29].

Abuse and dependence. In 32 recreational sedative users, single 10, 20 and 30 mg doses produced drug-liking scores well above placebo and not different from suvorexant 40 mg or zolpidem 30 mg [3], and lemborexant is in Schedule IV [1]. Animal and human studies found no physical dependence, and there was no rebound insomnia after stopping [1].

Other findings. Lemborexant did not prolong the QTc interval at 5 times the top dose, and multiple doses up to 75 mg mainly caused dose-dependent somnolence [1]. Malformations appeared in rats only at more than 300 times the human exposure, and in breast milk the infant dose is under 2% of the mother's [1].

Lemborexant is cleared mainly by CYP3A4, and the label advises avoiding strong or moderate CYP3A inhibitors (such as itraconazole, clarithromycin, fluconazole and verapamil) and strong or moderate inducers (such as rifampin, carbamazepine, St John's wort and modafinil), and capping the dose at 5 mg with weak inhibitors [1]. It lowers exposure to CYP2B6 substrates such as bupropion and methadone, so their effect should be watched [1]. Alcohol raises its levels and adds to its impairment [28], and the label advises against alcohol and against combining it with other insomnia drugs or central depressants such as benzodiazepines, opioids and tricyclics [1].