Morpheus and the Silver Bullet: How DORAs Could Help Transform the Quest for Sleep

Chris King PDF (2026)

Insomnia Toll: Dementia and Comorbidities

Insomnia is an endemic, to epidemic, problem in urban societies with existential pressures on the individual, including work anxieties, relationships, financial worries and health, let alone complete uncertainty about our continued survival, in an urban atmosphere of nocturnal activity divorced from natural circadian rhythms. Between 10% and 30% of adults have insomnia at any given point in time, and up to half of people have insomnia in a given year. About 6% of people have insomnia that is not due to another problem and lasts for more than a month. People over the age of 65 are affected more often than younger people. Women are more often affected than men. Descriptions of insomnia occur at least as far back as ancient Greece.

Short sleepers (<6h) have advanced rates of dementia despite good exercise (Bloomberg et al. 2023) compared with optimal (6-8h) over 10 years. After adjusting for select co-morbidities, primary insomnia remained a significant factor for developing dementia, associated with a 2.14-fold increase in dementia risk (Hung et al.  2018). Estimates of insomnia prevalence in the elderly range from 25 to >50%. The medical and socioeconomic implications of insomnia are considerable, and include increased mortality, development of psychiatric or general comorbidities (Noble et all 1988, Patel et al. 2018).

Hung et al. (2018) note regarding insomnia’s very negative toll on health, that their primary insomnia cohort had a higher prevalence of diabetes, dyslipidemia, hypertension, coronary heart disease, chronic liver disease, and chronic kidney disease at baseline. After adjusting for select co-morbidities, primary insomnia remained a significant predisposing factor for developing dementia, and was associated with a 2.14-fold (95% confidence interval, 2.01–2.29) increase in dementia risk. We also found a higher risk of dementia in younger patients.

Nobel et al. (1998) note: Insomnia, the inability to initiate and/or maintain sleep, is estimated to affect about one-third of the general population, with up to about one-quarter of those affected experiencing severe sleep deficit. Estimates of insomnia prevalence in the elderly range from 25 to >50%. The medical and socioeconomic implications of insomnia are considerable, and include increased mortality, development of psychiatric or general comorbidities, reduced productivity and/or work attendance and increased probability of involvement in accidents. … In conclusion, zopiclone is now well established as an effective and well tolerated hypnotic agent.

Pharmaceutical Remedies

Aside rom the central dogma of CBT-I or cognitive behavioural therapy for insomnia, as a first line treatment, Wikipedia cites lemborexant, a recently released (in 2018), dual orexin receptor antagonist, or DORA, as well as the well known GABAergic sedative Z-drug zopiclone, as key agents for psychopharmaceutical treatment. Here we review why the DORAs have a critical advantage, both with effective sleep onset and maintenance, and two critical factors – overall natural sleep quality and absence of physical dependence. Lemborexant is now an unfunded prescription drug in NZ under the name Dayvigo. Lemborexant, with its manifestation of intense dreaming as well as deep sleep unlike benzodiazepines, fulfils the ancient role of Morpheus as the god of dreams. In Ovid's Metamorphoses, he is the son of Somnus (Sleep, the Roman counterpart of Greek Hypnos).

Orexin / hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy is caused by a lack of orexin in the brain due to destruction of the cells that produce it. There are 50,000–80,000 orexin-producing neurons in the human brain, located predominantly in the lateral hypothalamus and perifornix. They project widely throughout the central nervous system. The two types of orexin, orexin-A, 33 amino acid residues long, with two intra-chain disulphide bonds and orexin-B, a linear 28 amino acid residue peptide, are both excitatory neuropeptides with approximately 50% sequence identity, produced by cleavage of a single precursor protein, prepro-orexin.  The orexin peptides bind to the two G-protein coupled orexin receptors, OX1 and OX2, with orexin-A binding to both OX1 and OX2 with approximately equal affinity while orexin-B binds mainly to OX2 and is 5 times less potent at OX1. OX2 plays a dominant role in wakefulness (especially in histaminergic neurons) with OX1 more involved in vigilance/anxiety circuits, though both contribute to overall arousal and reward. OX1R primarily signals via Gq, while OX2R uses Gq and Gi/o, leading to distinct downstream effects like regulating sleep/wake cycles, mood, and appetite.

Fig 1: Orexin and its DORAs.

Orexin receptors are strongly conserved and their evolution goes back to the common ancestor of all metazoa also occurring in placozoa and cnidaria (Yañez-Guerra, Thiel & Jékely 2022), as neuropeptide precursors are also present in choanoflagellates. Orexins share evolutionary affinities  with the allatotropin neuropeptide system in arthropods (Alzugaray et al. 2019). The ventrolateral preoptic nucleus (VLPO) in the anterior hypothalamus is active during sleep, particularly during non-rapid eye movement sleep (NREM sleep) and inhibits orexin neurons, forming a flip-flop seesaw (6). (5, 7) comparison of current DORAs.

Lemborexant is a dual antagonist of the orexin OX1 and OX2 receptors with relative selectivity for OX2, which suppresses both REM and non-REM sleep drive. It has four key advantages over GABAergic sleep medications: (1) rapid sleep onset, addressing sleep initiation insomnia, (2) a long enough half life to address sleep maintenance insomnia, (3) a sleep quality profile, close to natural sleep, including both deep NREM and REM sleep, (4)  no established evidence for physical tolerance or dependence in up to a year of use.  Some people do have wild dreams, which could be partly a response to switching from GABAergic agents that can cause a rebound of REM on cessation.

Because DORAs and Z-drugs operate on different systems, they are non-interactive. There are both positive patient reports and research studies concerning compbined use.  In a currently ongoing trial of lemborexant, I have found 5 mg to provide a deep natural sleep without the side effects of sedatives on sleep quality. However, I have found it helpful to have a 1.8 mg quarter-zopiclone ready, because I tend to awaken up to five times a night to empty my bladder and may end up staying awake, even on lemborexant. However this reduces the effective need for zopiclone.

Side effects of lemborexant include somnolence, headache, nightmares or abnormal dreams, sleep paralysis and hypnagogic hallucinations. It produces drug-liking responses similar to those of zolpidem and suvorexant in recreational sedative drug users. It is a controlled substance in the United States and is considered to have a low misuse potential.  

Medsafe NZ state: Dependence In both animal studies and clinical trials evaluating physical dependence, chronic administration of lemborexant did not produce withdrawal signs or symptoms upon drug discontinuation. This suggests that lemborexant does not produce physical dependence.

Reviews on drugs.com give lemborexant 5.4/10 on 319 reviews, by comparison with eszopiclone at 5.7/10 on 450 reviews, showing neither are ideal. Complaints about lemborexant centre on its capacity to induce alarming dream-like states on a first experience, giving it 1/10 each, with the other half of reviews giving it 9 or 10/10.

1/10 “I thought I had dropped into a live-in nightmare two times in one night. It scared me so badly when I finally woke up, I swore I would never take this drug again. It was the most horrific dream I've ever had”. 

1/10 “I took my first 5 mg Dayvigo two nights ago. After 90 minutes of sleep, I awakened with horror as I hallucinated a crazy scary dream. Felt paralyzed and wanted to scream but could not make a sound. Was able to touch my husband's arm and wake him. He said he had never seen such terror in my eyes”.

1/10 “I’ve taken this Dayvigo two nights in a row, and I’ve been awake probably 6-7 times per night. The only time it feels like it’s being most effective is when I need to be waking up."

10/10 “I have severe insomnia and have had no luck with Ambien (zolpidem), Lunesta (ezopiclone), trazodone, and others. None of them worked. Dayvigo 10 mg did. I have finally gotten sleep. No side effects. The first day I was a little groggy, but that went away the next day. I do wake up a few times in the night to go pee, but I fall back to sleep quickly, which has NEVER happened for me.

10/10 "I have had very bad insomnia for years. I have tried everything. Ambien and Lunesta make me forget everything. I started on Dayvigo 5mg and found that it made me feel like I was in a trance and I had some GI issues, however, once I increased it to the 10mg dose, I fell asleep fast, got very restful sleep. I have no side effects, and while I may not sleep 8 hours each night, the sleep that I am getting is more restful. It feels like I am sleeping naturally like I did once upon a time!”

10/10 "I have never been able to just lay down and sleep. As a child, I hated going to bed because of that. I have tried everything - Ambien, flurazepam, every holistic sleep aid, with little or no help. Even if I eventually fall asleep, I don't stay asleep. My doctor gave me the Dayvigo 5mg sample box, advising I take one to begin, which I did. I slept like a baby. I woke up seven hours later to go to the bathroom and went back to bed, sleeping another 3 hours. I was so sleep-deprived. I feel a little groggy from sleeping so much and am glad I didn't take two of the 5mg. I am beyond happy to find something that works for me."

Study Reports

Expert opinion (Inoue & Koebis 2025): Lemborexant, with relative selectivity for the orexin receptor type 2, offers robust efficacy for both sleep initiation and maintenance. Its pharmacokinetic profile yields a quick onset and steep decline in plasma levels, helping minimize next-morning residual effects despite a long terminal half-life. Network meta-analyses demonstrate improvements in subjective and objective sleep measures, with lemborexant often ranking highest among hypnotics.

The efficacy of lemborexant in clinical trials (Inoue & Koebis 2025):  Two Phase 3 placebo-controlled, double-blind studies have demonstrated that lemborexant significantly improved sleep onset difficulties and sleep maintenance difficulties, both subjectively and objectively, in individuals with insomnia, and that its effects were sustained over both short-term (1month) and long-term (up to 12 months) use.

Expert opinion (Muehlan et al. 2020): In general, the drugs described have a similar effect on sleep characteristics although their pharmacokinetic variables differ. ORAs have the potential to revolutionize the pharmacological treatment of insomnia because they not only improve sleep, but, in addition, appear to have no dependence – and tolerance-inducing effects, which makes them suitable for long-term-treatment. The safety and tolerability profile of ORAs clearly differ from those of more traditional sleep- promoting drugs. Further research is needed to demonstrate benefits to patients suffering from insomnia disorder, e.g., with respect to improving not only sleep but also daytime functioning. In addition, ongoing and future research will show whether ORAs may have beneficial effects in patients with various psychiatric and neurodegenerative disorders, including Alzheimer’s disease.

Discussion (Gotfried et al. 2024)  Post hoc analyses of older adults (aged ≥ 65 years) from three clinical studies revealed significant benefits of LEM on aspects of sleep and morning functioning versus PBO. Notably, LEM improved sleep maintenance during the second half of the night. Further, after middle-of-the- night awakening, subjects taking LEM10 returned to sleep significantly faster than those taking ZOL. ... Specifically, postural stability, next-day driving performance, and cognition were generally better or associated with less impairment with LEM versus ZOL.

Return-to-sleep Latency was shortest for subjects who received LEM10 (10.6 min), followed by LEM5 (21.1 min) and zolpidem (22.5 min) compared with those who received placebo (41.3 min).

Conclusion (Waters 2022): Lemborexant can be recommended to treat insomnia disorder when pharmacological treatment is warranted. It has demonstrated efficacy in clinical trials and is likely better tolerated than most currently available treatment options.

Long-term safety and efficacy of lemborexant in subjects with irregular sleep-wake rhythm disorder and Alzheimer’s disease dementia (Moline et al. 2020) Irregular Sleep-Wake Rhythm Disorder (ISWRD) is a common circadian rhythm sleep disorder among individuals with Alzheimer’s disease dementia (AD-D). In subjects with AD-D and ISWRD treated with LEM10, moderate improvement in SDI-ts continued to be observed over time. Ragsdale et al. (2025) examine the relationship between sleep and Alzheimer’s disease (AD), and highlight a need for understanding glymphatic and/or other mechanism of clearance during sleep. They explore dual orexin receptor antagonists (DORAs) potential to mitigate AD sleep disturbances and enhance clearance.

Comparative efficacy and safety of daridorexant, lemborexant, and suvorexant for insomnia (Kishi et al. 2025). This included daridorexant 25 or 50 mg/day, lemborexant 5 or 10 mg/day (LEM5), suvorexant 20 mg/day (15 mg/day for people ≥65years), and placebo, all active-treatments outperformed placebo in terms of all efficacy outcomes. Considering that there is no evidence that DORAs are associated with physiological tolerance, withdrawal symptoms, or rebound insomnia when abruptly discontinued, and that sleep architecture is not adversely affected, the DORAs appear to be a favorable choice in managing insomnia disorder in adults.

Fig 2: Glutamate and GABA Dynamics

We now compare the findings on DORAs with traditional GABAergic sedatives, particularly benzodiazepines, such as temazepam, and the more recent Z-drugs, such as zopiclone, and zolpidem, which were designed to be less prone to developing tolerance and physical dependence. In sleep laboratory studies, temazepam, which is regarded as a short acting benzodiazepine, with a half life of 8-20 hours, significantly decreased the number of nightly awakenings, but has the drawback of distorting the normal sleep pattern towards stage 2 NREM as opposed to deep stage 4 NREM and dreaming REM, both of which are key to the restorative power of natural sleep. Benzodiazepine use can result in both rebound insomnia and in extreme cases, seizures. Z-drugs were developed to try to avoid these disadvantages , but still have dependence issues so that GPs are reluctant to prescribe them long term on a daily basis, meaning that people with long term insomnia are not having their needs addressed. Z-drugs do have a better sleep profile but do suppress REM to the extent that rebound REM is experienced, as well as developing tolerance and dependence. Z-drugs also have a shorter half life, with zopiclone around 5 hours, and zolpidem 2-3 hours, so they can relieve insomnia and leave one refreshed in he morning.

We now explore how sedative GABAergic agents affect the conscious brain. What this establishes is that although GABAergic sedatives can be used to treat insomnia, they are trying to do so, fig 3, by pushing the natural balance between glutamate excitation and GABA inhibition – imposing inhibition on a relatively brain wide basis to attempt to induce sleep. This is feasible because natural sleep also involves a widespread increase in GABA inhibition, but it is not addressing the key switch in the hypothalamus that is key to switching between sleep and wakefulness. This is precisely what the DORAs have set out to do with some success.

Fig 3: While DORAs involve the switch between waking and sleeping states, GABAergic sedatives attempt to push the overall glutaminergic balance between glutamate and GABA to one side, reducing anxiety and promoting sleep..

Glutamate neurons excite, making action potentials more likely, in the post synaptic cell, while GABA interneurons inhibit, making them less likely through hyperpolarization, creating a crucial balance (Excitation/Inhibition or E/I balance) in neural circuits, noted in gamma waves in EEG, where glutamate excites pyramidal cells and GABAergic interneurons control their timing, by phase-shifted inhibition, ensuring proper brain function and avoiding seizures. Fig 2 shows this behaviour in pairs of glutamate and GABA neurons (1) with tonic GABA action potentials negatively hyperpolarising and thus inhibiting neighbouring glutamate neurons (Marchionni & Maccaferri 2009) and (2) in multiple connections in cortical layers. This dynamic interplay also guides embryogenic neuron development, with both neurotransmitters influencing cell migration and circuit formation. GABAergic interneurons primarily hyperpolarize pyramidal cells, making them more negative and less likely to fire action potentials down their long axons, connecting to other areas of the brain. Glutamate and GABA are cosmologically abundant molecules prominent in the Murchison meteorite and have complementary syntheses via glutamine in glial cells serving both neuronal types (3). Glutamate and GABA also have long range excitatory and (4) glutamatergic and GABAergic projections involved in mood regulation and the reward pathway (Sarawagi, Soni & Patel 2021).

The GABAa ionotropic receptor (5) is a pentamer of five sub-component proteins facilitating Cl^– flow. (b) Benzodiazepines such as temazepam bind to the same allosteric modulation site between α1 and γ2 components, enhancing the binding of GABA and thus chloride flow. Z-drugs such as zopiclone bind to the α subunit with short-acting zaleplon binding selectively to α1. Valerenic acid, in the herbal sleep remedy valerian and the synthetic sedative loreclezole, which again are structurally unrelated, bind to a site on the β2 protein. This explains why benzodiazepines and Z-drugs show cross-tolerance, although differences between the binding sites appear to make for reduced tolerance in Z-drugs and significantly reduced withdrawal symptoms. The older barbiturates exemplified by Phenobarbital bind to multiple GABA receptor sites but also inhibit excitatory glutamate AMPA receptors adding to their sedative effects. The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABAa receptor, and also produces different effects on binding, with the benzodiazepines increasing the frequency of the chloride channel opening, while barbiturates increase the duration of chloride channel opening when GABA is bound. Since these are separate modulatory effects, they can both take place at the same time multiplicatively, so the combination of benzodiazepines with barbiturates is strongly synergistic, and thus dangerous.

Dependence with Zopiclone Medsafe Prescriber Update 16: 20–22 July 1998

Dependence and withdrawal effects with zopiclone do occur, although rarely. These effects can occur in people without prior substance dependence and who are taking the recommended dose.

Zopiclone (Imovane) is indicated for the short-term treatment of insomnia and appears to be associated with a very low risk of dependence, rebound insomnia, and withdrawal problems. Nevertheless some individuals do become dependent on zopiclone, and many of these have not experienced substance dependence or abuse previously. The approved data sheet for Imovane advises no more than 4 weeks continuous treatment, and a maximum dose of 7.5mg (1 tablet) a day.

Fig 4: BPAC survey data in 2021 shows NZ doctors opinions on the safety of zopiclone and the Medsafe recommendations  to restrict zopiclone use to short-term only, reflect the lack of real medical evidence for harmful effects, such as loss of efficacy due to tolerance, or significant rebound effects in longer term use, albeit with a small but significant cohort of long term users.

An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia (Roth et al. 2005), note in an evaluation of eszopiclone over 12 months in patients with chronic primary insomnia. 

Results: Patients who were initially randomized to double-blind placebo and then switched to open-label eszopiclone (n=111) significantly reported the following: (1) decreased sleep latency, wake time after sleep onset, and number of awakenings; (2) increased total sleep time and sleep quality; and (3) improved ratings of daytime ability to function, alertness and sense of physical well-being compared to baseline (P≤ 0.0001 all monthly endpoints). There was no evidence of tolerance on any measure in either group. These subjects (n=360) sustained the double-blind treatment gains for all sleep and daytime parameters, with further significant improvement in a number of measures. Eszopiclone was well tolerated in both groups; unpleasant taste was the only undesirable effect reported by > 5% of patients.

Conclusions: The significant improvements in sleep and daytime function were evident in those switched from double-blind placebo to 6 months of open-label eszopiclone therapy and were sustained during the 6 months of open-label treatment for those receiving prior double- blind eszopiclone. During 12 months of nightly treatment, eszopiclone 3 mg was well tolerated; tolerance was not observed.

This shows zopiclone with a short 5 hour half life can safely be prescribed daily long term as long as there is not a gradual increase in consumption. Chiral eszopiclone at 3mg is equivalent to racemic zopiclone at 6 mg, so is close to to a full 7.2 mg tablet.

A Comparative Assessment of the Risks and Benefits of Zopiclone Hajak G (1999)

Conclusons: In over 15 years of clinical usage of zopiclone, the benefits associated with its use appear to far outweigh the risks, notably those of withdrawal or dependence. Results from a large number of studies indicate that rebound insomnia after withdrawal of zopiclone is possible but infrequent. This contrast with most benzodiazepines, with which as many as one-third of long term users may experience a withdrawal syndrome, even after tapered withdrawal.

Nightly Treatment of Primary Insomnia With Eszopiclone for Six Months Walsh et al. (2007)

Throughout 6 months, eszopiclone improved all of the components of insomnia as defined by DSM-IV, including patient ratings of daytime function. This placebo-controlled study of eszopiclone pro- vides compelling evidence that long-term pharmacologic treatment of insomnia is efficacious.

Melatonin

Fig 5: Melatonin half lives (Mun et al. 2024)

Melatonin in both immediate and long release forms is also an aid to ensuring circadian rhythms are phased with one’s sleep cycle, thus promoting sleep. Immediate release has a very short half life of 20-60 mins but a rapid onset valuable for sleep initiation. Extended release has a 3-4 hour half life good for sleep maintenance, but takes up to an hour to become effective. A careful mix of the two is advantageous. In NZ natural melatonin 3m requires a prescription, while slow release 2 mg is available through a pharmacy.

Combined Use

Because DORAs and Z-drugs operate on different systems, they are non-interactive. There are both positive patient reports and research studies concerning combined use. 

Patient Report I'm 70, female, 60 years behind on my sleep, but finally found a solution. Me and my siblings are very poor sleepers, and it was only getting worse. It would take me 3-4 hours to fall asleep, I missed that class on how to fall asleep. So, my stress level was soaring, I developed cardiac arrythmias, and was terrified. I knew my arrythmias wouldn't settle down if I didn't get some sleep. One night I was desperate so I decided to take both Dayvigo 10mg and Zopiclone 7.5mg together. Magic!!! They work on different aspects of the sleep cycle which is just what I needed. I talked to my GP to let him know what I took, and he was okay with it. He gave me a plan...keep the Dayvigo at 10mg, slowly reduce the Zopiclone to the lowest dose that still works. ...  I settled on 3.75mg. ... I'm beyond thrilled with the results. I sleep every night now, arrythmias are totally gone! I have good energy in the day, though I still need my coffee to perk up. I will keep using these meds as long as possible. I hope this can help someone else too.

Research Study People With OSA With a Low Arousal Threshold Who Have Difficulty Sleeping (ELOSA) Insomnia and obstructive sleep apnoea (OSA) are very common conditions, collectively estimated to affect 2 billion people globally. 30 to 40% of patients with chronic insomnia also fulfil the diagnostic criteria for OSA. These people can be particularly challenging to treat with conventional therapy approaches. Accordingly, this study aims to increase the arousal threshold using a combination approach with a GABAergic and an orexin agent in appropriately selected individuals.

Here is my own report on lemborexant. Because I am hyper-vigilant and 81 years of age, I can find sleep onset difficult, but when I get a first hour of natural sleep if I am not anxious, even though I repeatedly wake up five times a night to urinate, I can generally get back to sleep afterwards. In a currently ongoing trial of lemborexant, I have found 5 mg to provide a deep relatively natural sleep, albeit with prominent episodes of intense paradoxical dreaming, without the ghostly half-awake features of GABAergic somnolence of sedatives on sleep quality, particularly when a small dose doesn't work. However, I have found it helpful to have a quarter-zopiclone (~1.8 mg) on hand, because when I first began taking it I would sometimes wake up alert after a few hours of very deep sleep. More recently this problem has diminished and I find it close to ideal. Nevertheless, this minimalist combined use, reduces the effective need for zopiclone to a minimum, taking advantage of its short half-life of circa 4.5 hours, to use later in the night than leborexant. 

References

Alzugaray M et al. (2019) The evolutionary History of the orexin/Allatotropin GpCR Family: from placozoa and Cnidaria to Vertebrata Sci. Repts. 9:10217 doi:10.1038/s41598-019-46712-9

Bloomberg  M et al. (2023) Joint associations of physical activity and sleep duration with cognitive ageing: longitudinal analysis of an English cohort study Lancet Healthy Longevity 2023; 4: e345–53.

Dayal S et al. (2021) Effect of hepatic impairment on pharmacokinetics, safety, and tolerability of lemborexant Pharmacol Res Perspect. 9:e00758. doi:10.1002/prp2.758

Gotfried M et al. (2024) Efficacy and safety of insomnia treatment with lemborexant in older adults: analyses from three clinical trials Drugs & Aging 41 741–752 doi:10.1007/s40266-024-01135-8.

Hajak G (1999) A Comparative Assessment of the Risks and Benefits of Zopiclone A Review of 15 Years' Clinical Experience Drug Safety (6): 457-469.

Hung C et al. (2018) Risk of dementia in patients with primary insomnia: a nationwide population-based case-control study BMC Psychiatry doi:10.1186/s12888-018-1623-0

Inoue Y & Koebis M (2025) Comprehensive understanding of the treatment of insomnia with lemborexant Expert Review of Clinical Pharmacology 18:10, 785–796 doi:10.1080/17512433.2025.2573364.

Kishi T et al. (2025) Comparative efficacy and safety of daridorexant, lemborexant, and suvorexant for insomnia: a systematic review and network meta-analysis Translational Psychiatry 15:211

Landry I et al. (2021) Pharmacokinetics, Pharmacodynamics, and Safety of the Dual Orexin Receptor Antagonist Lemborexant: Findings From Single-Dose and Multiple-Ascending-Dose Phase 1 Studies in Healthy Adults Clinical Pharmacology in Drug Development 10(2) 153–165 doi:10.1002/cpdd.817

Marchionni I & Maccaferri G (2009) Quantitative dynamics and spatial profile of perisomatic GABAergic input during epileptiform synchronization in the CA1 hippocampus J Physiol 587.23 5691–5708.

Moline M, Bsharat M & Cheng J (2020) Long-term safety and efficacy of lemborexant in subjects with irregular sleep-wake rhythm disorder and Alzheimer’s disease dementia  Alzheimer’s Dement. 16 (Suppl. 9):e039039. doi:10.1002/alz.039039.

Muehlan C et al. (2020) Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders Expert Opinion on Drug Metabolism & Toxicology 16:11 1063-1078, doi:10.1080/17425255.2020.1817380.

Mun et al. (2024) A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults Journal of Dietary Supplements, 21:2, 182-194, doi:10.1080/19390211.2023.2206475

Noble S et al. (1998) Zopiclone An Update of its Pharmacology, Clinical Efficacy and Tolerability in the Treatment of Insomnia Drugs Feb; 55 (2): 277-302.

Patel D et al. (2018) Insomnia in the elderly J Clin Sleep Med. 14(6): 1017–1024.

Ragsdale S et al. (2025) Dual orexin receptor antagonists as promising therapeutics for Alzheimer’s disease Biological Timing and Sleep 2:11 doi:10.1038/s44323-025-00025-5.

Roth T et al. (2005) An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia Sleep Medicine 6 (2005) 487–495.

Sarawagi A, Soni N & Patel A (2021) Glutamate and GABA Homeostasis and Neurometabolism in Major Depressive Disorder Front. Psychiatry 12:637863. doi: 10.3389/fpsyt.2021.637863

Soya S & Sakurai T (2020) Evolution of Orexin Neuropeptide System: Structure and Function Front. Neurosci. 14
doi:10.3389/fnins.2020.00691

Walsh et al. (2007) Nightly Treatment of Primary Insomnia With Eszopiclone for Six Months: Effect on Sleep, Quality of Life, and Work Limitations SLEEP 30(8):959-968.

Wang C et al. (2018) The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases Front. Mol. Neurosci. 11:220. doi:10.3389/fnmol.2018.00220.

Waters K (2022) Review of the Efficacy and Safety of Lemborexant, a Dual Receptor Orexin Antagonist (DORA), in the Treatment of Adults With Insomnia Disorder Annals of Pharmacotherapy 56(2) 213–221 doi:10.1177/10600280211008492.

Wong K et al. (2011) Orexins and their receptors from fish to mammals: A comparative approach General and Comparative Endocrinology 171 (2011) 124–130.

Yañez-Guerra L, Thiel D & Jékely G (2022)  Premetazoan Origin of Neuropeptide Signaling Mol. Biol. Evol. 39(4) msac051
doi:10.1093/molbev/msac051.