Orexin (hypocretin) and addiction

Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior

Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R. M., Tanaka, H., Williams, S. C., Richardson, J. A., Kozlowski, G. P., Wilson, S., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)80949-6 · Cited by 5,501 · see citing works

The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity

de Lecea, L., Kilduff, T. S., Peyron, C., Gao, X.-B., Foye, P. E., Danielson, P. E., Fukuhara, C., Battenberg, E. L. F., Gautvik, V. T., Bartlett, F. S., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.1.322 · Cited by 3,878 · see citing works

Reduced Number of Hypocretin Neurons in Human Narcolepsy

Thannickal, T. C., Moore, R. Y., Nienhuis, R., Ramanathan, L., Gulyani, S., Aldrich, M., Cornford, M., & Siegel, J. M. (2000) · Neuron · doi:10.1016/s0896-6273(00)00058-1 · Cited by 2,089 · see citing works

A role for lateral hypothalamic orexin neurons in reward seeking

Harris, G. C., Wimmer, M., & Aston-Jones, G. (2005) · Nature · doi:10.1038/nature04071 · Cited by 1,311 · see citing works

Motivational activation: a unifying hypothesis of orexin/hypocretin function

Mahler, S. V., Moorman, D. E., Smith, R. J., James, M. H., & Aston‐Jones, G. (2014) · Nature Neuroscience · doi:10.1038/nn.3810 · Cited by 385 · see citing works

Parallel circuits from the bed nuclei of stria terminalis to the lateral hypothalamus drive opposing emotional states

Giardino, W. J., Eban-Rothschild, A., Christoffel, D. J., Li, S.-B., Malenka, R. C., & de Lecea, L. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0198-x · Cited by 252 · see citing works

Increased Number and Activity of a Lateral Subpopulation of Hypothalamic Orexin/Hypocretin Neurons Underlies the Expression of an Addicted State in Rats

James, M. H., Stopper, C. M., Zimmer, B. A., Koll, N. E., Bowrey, H. E., & Aston‐Jones, G. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.07.022 · Cited by 191 · see citing works

A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?

James, M. H., Mahler, S. V., Moorman, D. E., & Aston‐Jones, G. (2016) · Current topics in behavioral neurosciences · doi:10.1007/7854_2016_57 · Cited by 171 · see citing works

Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy

Thannickal, T. C., John, J., Shan, L., Swaab, D. F., Wu, M.-F., Ramanathan, L., McGregor, R., Chew, K., Cornford, M. E., Yamanaka, A., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aao4953 · Cited by 138 · see citing works

NIDA’s medication development priorities in response to the Opioid Crisis: ten most wanted

Rasmussen, K., White, D. A., & Acri, J. B. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-018-0292-5 · Cited by 128 · see citing works

Diurnal fluctuation in the number of hypocretin/orexin and histamine producing: Implication for understanding and treating neuronal loss

McGregor, R., Shan, L., Wu, M., & Siegel, J. M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0178573 · Cited by 49 · see citing works

Hypocretin modulation of drug-induced synaptic plasticity

Baimel, C., & Borgland, S. L. (2012) · Progress in brain research · doi:10.1016/b978-0-444-59489-1.00008-2 · Cited by 40 · see citing works

Orexin Reserve: A Mechanistic Framework for the Role of Orexins (Hypocretins) in Addiction

James, M. H., & Aston‐Jones, G. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.06.027 · Cited by 50 · see citing works

Trigeminal nerve stimulation: a current state-of-the-art review

Powell, K., Lin, K., Tambo, W., Saavedra, A. P., Sciubba, D. M., Abed, Y. A., & Li, C. (2023) · Bioelectronic Medicine · doi:10.1186/s42234-023-00128-z · Cited by 50 · see citing works

Physiological Role of Orexinergic System for Health

Villano, I., Marra, M. L., Maio, G. D., Monda, V., Chieffi, S., Guatteo, E., Messina, G., Moscatelli, F., Monda, M., & Messina, A. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph19148353 · Cited by 47 · see citing works

Brain regulation of hunger and motivation: The case for integrating homeostatic and hedonic concepts and its implications for obesity and addiction

Morales, I. (2022) · Appetite · doi:10.1016/j.appet.2022.106146 · Cited by 39 · see citing works

The cognitive (lateral) hypothalamus

Sharpe, M. J. (2023) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2023.08.019 · Cited by 38 · see citing works

Whole Brain Mapping of Orexin Receptor mRNA Expression Visualized by Branched In Situ Hybridization Chain Reaction

Tsuneoka, Y., & Funato, H. (2024) · eNeuro · doi:10.1523/eneuro.0474-23.2024 · Cited by 31 · see citing works

New directions in modelling dysregulated reward seeking for food and drugs

Brown, R. M., Dayas, C. V., James, M. H., & Smith, R. J. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.10.043 · Cited by 26 · see citing works

Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking

Giannotti, G., Mottarlini, F., Heinsbroek, J. A., Mandel, M. R., James, M. H., & Peters, J. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02161-z · Cited by 25 · see citing works

The abuse potential of lemborexant, a dual orexin receptor antagonist, according to the 8 factors of the Controlled Substances Act

Moline, M. L., Asakura, S., Beuckmann, C. T., Landry, I. S., Setnik, B., Ashworth, J., & Henningfield, J. E. (2023) · Psychopharmacology · doi:10.1007/s00213-023-06320-y · Cited by 25 · see citing works

Sleep-mediated regulation of reward circuits: implications in substance use disorders

Guo, R., Vaughan, D. T., Rojo, A. L. A., & Huang, Y. H. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-022-01356-8 · Cited by 24 · see citing works

Effect of a dual orexin receptor antagonist on Alzheimer's disease: Sleep disorders and cognition

Zhou, M., & Tang, S. H. (2023) · Frontiers in Medicine · doi:10.3389/fmed.2022.984227 · Cited by 20 · see citing works

Contribution of hypothalamic orexin (hypocretin) circuits to pathologies of motivation

Mohammadkhani, A., Mitchell, C. S., James, M. H., Borgland, S. L., & Dayas, C. V. (2024) · British Journal of Pharmacology · doi:10.1111/bph.17325 · Cited by 20 · see citing works

Sleep disturbance in substance use disorders: the orexin (hypocretin) system as an emerging pharmacological target

Gyawali, U., & James, M. H. (2022) · Neuropsychopharmacology · doi:10.1038/s41386-022-01404-3 · Cited by 17 · see citing works

Involvement of orexin-2 receptors in the CA1 region of the hippocampus in the extinction and reinstatement of methamphetamine-induced conditioned place preference in the rats

Amirteymori, H., Veisi, A., Khaleghzadeh‐Ahangar, H., Mozafari, R., & Haghparast, A. (2022) · Peptides · doi:10.1016/j.peptides.2022.170926 · Cited by 13 · see citing works

Effects of new hypnotic drugs on cognition: A systematic review and network meta-analysis

Zhou, M., Liu, R., Tang, J., & Shi, T. (2023) · Sleep Medicine X · doi:10.1016/j.sleepx.2023.100094 · Cited by 11 · see citing works

Recent advances in drug discovery efforts targeting the sigma 1 receptor system: Implications for novel medications designed to reduce excessive drug and food seeking

Knowles, L. G., Armanious, A. J., Peng, Y., Welsh, W. J., & James, M. H. (2023) · Addiction Neuroscience · doi:10.1016/j.addicn.2023.100126 · Cited by 10 · see citing works

Orexin-mediated motivated arousal and reward seeking

Bjorness, T. E., & Greene, R. W. (2024) · Peptides · doi:10.1016/j.peptides.2024.171280 · Cited by 10 · see citing works

Emerging medications and pharmacological treatment approaches for substance use disorders

Raymond, J. S., Athanasopoulos, A. G., Badolato, C. J., Doolan, T. M., Scicluna, R. L., Everett, N. A., Bowen, M. T., & James, M. H. (2024) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2024.173952 · Cited by 8 · see citing works

Machine learning models to predict ligand binding affinity for the orexin 1 receptor

Zhang, V. Y., O’Connor, S. L., Welsh, W. J., & James, M. H. (2023) · Artificial Intelligence Chemistry · doi:10.1016/j.aichem.2023.100040 · Cited by 7 · see citing works

Sex-dimorphic functions of orexin in neuropsychiatric disorders

Zhang, J., Jin, K., Chen, B., Cheng, S., Jin, J., Yang, X., Lü, J., & Song, Q. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e36402 · Cited by 7 · see citing works

Effects of suvorexant on diurnal cortisol and patient-reported stress during opioid withdrawal in a randomized trial

McKendrick, G., Clapham, C., Zipunnikov, V. M., Ellis, J. D., Finan, P. H., Dunn, K. E., Strain, E. C., Wolinsky, D., & Huhn, A. S. (2025) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2025.107570 · Cited by 6 · see citing works

Contribution of Visceral Systems to the Development of Substance Use Disorders: Translational Aspects of Interaction between Central and Peripheral Mechanisms

Peregud, D., & Gulyaeva, N. V. (2024) · Biochemistry (Moscow) · doi:10.1134/s0006297924110026 · Cited by 6 · see citing works

Effects of inhibiting the orexin system on nicotine reward memory and fear memory

Cui, P., Wu, D., Dong, J., Chen, Y. F., Feng, J., Liu, X., Chen, Z., Ge, J., & Liu, J. (2025) · Neuropharmacology · doi:10.1016/j.neuropharm.2025.110523 · Cited by 5 · see citing works

Dual Orexin Receptor Antagonists (DORAs) as an Adjunct Treatment for Smoking Cessation

Hamidovic, A. (2022) · CNS Drugs · doi:10.1007/s40263-022-00918-0 · Cited by 5 · see citing works

Orexin (Hypocretin) Signaling in the Basolateral Amygdala Contributes to Individual Differences in Stress Sensitivity

Gyawali, U., & James, M. H. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.02.957 · Cited by 5 · see citing works

Whole-brain mapping of afferent and efferent connections of lateral hypothalamic orexinergic neurons in mice

Du, J., Du, Z., Che, Y., Liu, D., Xu, Y., Zhang, J., Zheng, X., & Guo, G. (2025) · Brain Research · doi:10.1016/j.brainres.2025.149921 · Cited by 4 · see citing works

Avian Orexin: Feed Intake Regulator or Something Else?

Ramser, A., & Dridi, S. (2022) · Veterinary Sciences · doi:10.3390/vetsci9030112 · Cited by 4 · see citing works

Dopamine Drives Feedforward Inhibition to Orexin Feeding System, Mediating Weight Loss Induced by Morphine Addiction

Li, H., Wang, S., Wang, D., Li, J., Song, G., Guo, Y., Yin, L., Tong, T., Zhang, H., & Dong, H. (2025) · Advanced Science · doi:10.1002/advs.202411858 · Cited by 4 · see citing works

The role of orexin receptors within the CA1 area in the acquisition and expression of methamphetamine place preference

Moshrefi, F., Farrokhi, A. M., Fattahi, M., Azizbeigi, R., & Haghparast, A. (2024) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2024.02.051 · Cited by 3 · see citing works

Effects of Traumatic Brain Injury on the Orexin/Hypocretin System

Somach, R. T., Lim, M. M., & Cohen, A. S. (2025) · Neurotrauma Reports · doi:10.1089/neur.2024.0111 · Cited by 2 · see citing works

Found in translation: orexin receptor antagonism for the treatment of opioid use disorder

Raymond, J. S., Vareed, R. D., Peters, J., & James, M. H. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03571-5 · Cited by 2 · see citing works

Rethinking anorexia nervosa through the lens of control, compulsion and reward: Neurobiological insights into addiction-like features via the dopaminergic, endocannabinoid, and orexinergic systems − A narrative review

Ziemichód, W., Kajka, N., Rząd, Z., Metelska, A., Janas-Kozik, M. H., Biała, G., Wilczyński, K. M., Grabowska, K., & Karakuła‐Juchnowicz, H. (2026) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2026.106615 · Cited by 2 · see citing works

Reduction of Orexin-A Is Associated With Anxiety and the Level of Depression of Male Methamphetamine Users During the Initial Withdrawal Period

Guo, L., Hu, A., Zhao, X., & Xiang, X. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.900135 · Cited by 2 · see citing works

Lemborexant (Dayvigo)

CADTH (2023) · Canadian Journal of Health Technologies · doi:10.51731/cjht.2023.624

Neurofunctional phenotyping to investigate the role of the orexin system at the intersection of opioid use disorder and insomnia: a protocol for a randomised, placebo-controlled clinical trial of lemborexant in patients with insomnia receiving buprenorphine

Marcus, M. M., Alattar, M., Chen, S., Sabo, R., Pignatello, T., Ruddley, J., Green, A. R., Swan, K., Keyser‐Marcus, L., Moeller, F. G., et al. (2025) · BMJ Open · doi:10.1136/bmjopen-2025-108613

Découverte et caractérisation de nouveaux réseaux neuronaux peptidergiques gouvernant l'homéostasie énergétique et glucidique.

Devère, M. (2024) · doi:10.70675/62dbac23ze16fz4a68z87a6zc72ab10e8d27

Brain Reward Dopaminergic Circuits Involved in Sleep Deficiency, Sleep Deprivation and Relapse to Psychostimulants: A Narrative Review of Preclinical and Clinical Evidence

Arana-Lechuga, D. Y., Pérez-Morales, M., & Sánchez-Escandón, O. (2026) · Current Behavioral Neuroscience Reports · doi:10.1007/s40473-026-00325-5

Opposing Control of Dopamine Neuron Excitability by Orexin (Hypocretin) Receptors 1 and 2

Gyawali, U., & James, M. H. (2026) · Biological Psychiatry · doi:10.1016/j.biopsych.2026.07.013

Perceived effectiveness, tolerability, and discontinuation of lemborexant in real-world use: Evidence from online patient reports

Armanious, A. J., Dunn, A. R., Martin, C. E., & James, M. H. (2026) · Sleep Medicine · doi:10.1016/j.sleep.2026.109264

The Hypocretin/Orexin System: Implications for Drug Reward and Relapse

Plaza‐Zabala, A., Maldonado, R. J., & Berrendero, F. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8255-z · Cited by 58 · see citing works

The role of orexin signaling in addiction

Deqi, C. (2014)

Multiple roles for orexin/hypocretin in addiction

Mahler, S. V., Smith, R. J., Moorman, D. E., Sartor, G. C., & Aston-Jones, G. (2012) · Progress in Brain Research · doi:10.1016/b978-0-444-59489-1.00007-0 · Cited by 215 · see citing works

Role of orexin/hypocretin in dependence and addiction

Sharf, R., Sarhan, M., & Dileone, R. (2009) · Brain Research · doi:10.1016/j.brainres.2009.08.028 · Cited by 110 · see citing works

Neural correlates and potential targets for the contribution of orexin to addiction in cortical and subcortical areas

Kourosh‐Arami, M., Gholami, M., Alavi-Kakhki, S. S., & Komaki‬, A. (2022) · Neuropeptides · doi:10.1016/j.npep.2022.102259 · Cited by 8 · see citing works