Sleep Disorder and its Treatment: From Nature to Laboratory

Mohit Varshney(1), Supriyo Saha(2*), Prinsa Prinsa(3), Vikash Jakhmola(4)

(1) Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun-248007, Uttarakhand
(2) Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun-248007, Uttarakhand
(3) Siddhartha Institute of Pharmacy, Sahastradhara Road, Near IT-Park, Dehradun, Uttarakhand
(4) Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun-248007, Uttarakhand
(*) Corresponding Author


Sleep is the natural cellular repair mechanism to improve and restore central neural mechanism, memory, hormonal imbalance, and finally, cell rejuvenation. Sleep disorder is characterized by insomnia, circadian rhythm disorder (CRD), sleep apnea, narcolepsy, parasomnia, and restless leg syndrome (RLS) or periodic limb movement disorder (PLMD). Both oversleeping and less sleeping are associated with sleep disorders (SD). Anxiety, schizophrenia, weight loss/gain, hypothyroidism, and oxidative stress are the most common outcomes of SD. There is also a genetic explanation behind circadian rhythmicity, circadian disorder, narcolepsy-cataplexy syndrome, fatal familial insomnia, and somnambulism. Excessive work pressure, stress, and consumption of caffeine and alcohol collectively push a person toward sleep deprivation. Anxiety, schizophrenia, weight loss/gain, hypothyroidism, and oxidative stress are the most common outcomes of SD. Adenosine, melatonin, dopamine, serotonin, gamma amino butyric acid (GABA), orexin, and histamine regulate SDs by various pathways. Among natural sources, Centella asiatica, Bacopa monnieri, Acorus calamus, Withania somnifera, Nardostachys jatamansi, Poria cocos is, Valeriana officinalis, Matricaria chamomilla, Lavandula angustifolia, Nelumbo nucifera, Melissa officinalis, Convolvulus pluricaulis, Camellia sinensis, Ziziphus jujube, Datura stramonium, Zhizhipus jujube, Passiflora incarnata, and Moringa oleifera showed remarkable effects on different forms of SDs through GABAA, serotonin, and melatonin receptors. Pramipexole, ropinirole, rotigotine, clonazepam, lorazepam, estazolam, zolpidem, lemborexant, daridorexant, and suvorexant showed its activity in the treatment of SDs as a dopamine agonist, inhibitor of GABAA receptor, dual orexin receptor antagonist, respectively. This article focused on the types of SDs, the effects of SDs on mental health, receptors involved in the sleep cycle, and the impact of natural molecules and synthetic molecules in the management of SDs.


Melatonin; Natural sources; Orexin; Sleep disorder; Synthetic molecules

Full Text:



Abad, V. C., & Guilleminault, C. (2003). Diagnosis and treatment of sleep disorders: a brief review for clinicians. Dialogues in Clinical Neuroscience, 5(4), 371–388.

Adib-Hajbaghery, M., & Mousavi, S. N. (2017). The effects of chamomile extract on sleep quality among elderly people: A clinical trial. Complementary Therapies in Medicine, 35, 109–114.

Alessi, C.A., Martin, J.L., Webber, A.P., Alam, T., Littner, M.R., Harker, J.O., & Josephson, K.R. (2008). More daytime sleeping predicts less functional recovery among older people undergoing inpatient post-acute rehabilitation. Sleep, 31(9), 1291-300. PMID: 18788654

Ashbrook, L. H., Krystal, A. D., Fu, Y., & Ptáček, L. J. (2019). Genetics of the human circadian clock and sleep homeostat. Neuropsychopharmacology, 45(1), 45–54.

Ayala‐Guerrero, F., & Medina, G. M. (2017). Effect of a medicinal plant (Passiflora incarnata L) on sleep. Sleep Science, 10(03), 96–100.

Bian, Z., Zhang, W., Tang, J., Fei, Q., Hu, M., Chen, X., Su, L., Fei, C., Ji, D., Mao, C., Tong, H., Yuan, X., & Lu, T. (2021), Mechanisms Underlying the action of Ziziphi spinosae semen in the treatment of insomnia: a study involving network pharmacology and experimental validation. Frontiers in Pharmacology, 12.

Brickley, S. G., Franks, N. P., & Wisden, W. (2018), Modulation of GABA A receptor function and sleep. Current Opinion in Physiology, 2, 51–57.

Cheah, K. L., Norhayati, M. N., Yaacob, L. H., & Rahman, R. A. (2021). Effect of Ashwagandha (Withania somnifera) extract on sleep: A systematic review and meta-analysis. PLOS ONE, 16(9), e0257843.

Chen, T., Hiyama, A., Muramatsu, M., & Hinotsu, A. (2022). The effect of lavender on sleep quality in individuals without insomnia. Holistic Nursing Practice, 36(4), 223–231.

Czeisler, C. A., Walsh, J. K., Roth, T., Hughes, R. J., Wright, K. P., Kingsbury, L., Arora, S., Schwartz, J., Niebler, G., & Dinges, D. F. (2005). Modafinil for Excessive Sleepiness Associated with Shift-Work Sleep Disorder. The New England Journal of Medicine, 353(5), 476–486.

Dang, A., Garg, A., & Rataboli, P. V. (2011). Role of Zolpidem in the management of insomnia. CNS Neuroscience & Therapeutics, 17(5), 387–397.

Dierickx, P., Van Laake, L. W., & Geijsen, N. (2017). Circadian clocks: from stem cells to tissue homeostasis and regeneration. EMBO Reports, 19(1), 18–28.

Dokkedal‐Silva, V., Kim, L. J., Morelhão, P. K., Galduróz, J. C. F., Tufik, S., & Andersen, M. L. (2020). Use of clonazepam in REM sleep behavior disorder: association with fall-related injuries and alternative treatments. Journal of Clinical Sleep Medicine, 16(4), 655–656.

Dubocovich, M. L. (2007). Melatonin receptors: Role on sleep and circadian rhythm regulation. Sleep Medicine, 8, 34–42.

Dzirasa, K., Ribeiro, S., Costa, R. M., Santos, L. M., Lin, S., Grosmark, A., Sotnikova, T. D., Gainetdinov, R. R., Caron, M. G., & Nicolelis, M. a. L. (2006), Dopaminergic control of Sleep–Wake states. The Journal of Neuroscience, 26(41), 10577–10589.

Feng, H., Wen, S., Qiao, Q., Pang, Y., Wang, S., Li, H., Cai, J., Zhang, K., Chen, J., Hu, Z., Luo, F., Wang, G., Yang, N., & Zhang, J. (2020). Orexin signaling modulates synchronized excitation in the sublaterodorsal tegmental nucleus to stabilize REM sleep. Nature Communications, 11(1).

França, A. S. C., Lobão-Soares, B., Muratori, L., Nascimento, G. J. F. D., Winne, J., Pereira, C. M., Jerônimo, S. M. B., & Ribeiro, S. (2015). D2 dopamine receptor regulation of learning, sleep and plasticity. European Neuropsychopharmacology, 25(4), 493–504.

Franken, P. (2013). A role for clock genes in sleep homeostasis. Current Opinion in Neurobiology, 23(5), 864–872.

Gobbi, G., & Comai, S. (2019), Differential function of melatonin MT1 and MT2 receptors in REM and NREM sleep. Frontiers in Endocrinology, 10.

Gottesmann, C. (2002). GABA mechanisms and sleep. Neuroscience, 111(2), 231–239.

Gray, N. E., Magaña, A. A., Lak, P., Wright, K. M., Quinn, J. F., Stevens, J. F., Maier, C. S., & Soumyanath, A. (2017). Centella asiatica: phytochemistry and mechanisms of neuroprotection and cognitive enhancement. Phytochemistry Reviews, 17(1), 161–194.

Han, A. H., Burroughs, C. R., Falgoust, E. P., Hasoon, J., Hunt, G., Kakazu, J., Lee, T., Kaye, A. M., Kaye, A. D., & Ganti, L. (2023). Suvorexant, a novel dual orexin receptor antagonist, for the management of insomnia. Health Psychology Research, 10(5).

Hondo, M., Nagai, K., Ohno, K., Kisanuki, Y., Willie, J. T., Watanabe, T., Yanagisawa, M., & Sakurai, T. (2010). Histamine‐1 receptor is not required as a downstream effector of orexin‐2 receptor in maintenance of basal sleep/wake states. Acta Physiologica, 198(3), 287–294. 1716.2009.02032.x

Iwasaki, K., Komiya, H., Kakizaki, M., Miyoshi, C., Abe, M., Sakimura, K., Funato, H., & Yanagisawa, M. (2018). Ablation of central serotonergic neurons decreased REM sleep and attenuated arousal response. Frontiers in Neuroscience, 12.

Jie, Z., Li, J., Liu, C., Gui, H., Yuan, C., & Zhang, Y. (2022). The role of intracerebral dopamine D1 and D2 receptors in sleep‐wake cycles and general anesthesia. Ibrain, 8(1), 48–54.

Kales, A., Bixler, E. O., Soldatos, C. R., Jacoby, J. A., & Kales, J. D. (1986). Lorazepam: Effects on sleep and withdrawal phenomena. Pharmacology, 32(3), 121–130.

Kalpesh, P., Mukeshkumar, N., Nishteswar, K. (2020). Central nervous system depressant activity of Jatamansi (Nardostachysjatamansi DC.) rhizome. Ayu. 41(4), 250–254. 251 20.

Kim, H., Park, I., Park, K., Park, S., Kim, Y. I., & Park, B. (2022). The Positive Effects of Poria cocos Extract on Quality of Sleep in Insomnia Rat Models. International Journal of Environmental Research and Public Health, 19(11), 6629.

Kim, S., Jo, K., Hong, K. T., Han, S. H., & Suh, H. J. (2019). GABA and l-theanine mixture decreases sleep latency and improves NREM sleep. Pharmaceutical Biology, 57(1), 64–72.

Lancel, M. (1999). Role of GABAA receptors in the regulation of sleep: initial sleep responses to peripherally administered modulators and agonists. SLEEP, 22(1), 33–42.

Lazarus, M., Chen, J., Huang, Z., Urade, Y., & Fredholm, B. B. (2017), Adenosine and sleep. In Handbook of experimental pharmacology (pp. 359–381).

Li, S., & Yang, J. (2020). Pitolisant for treating patients with narcolepsy. Expert Review of Clinical Pharmacology, 13(2), 79–84.

Lin, C., Chiang, C., Tseng, M., Tam, K., & Loh, E. (2023). Effects of quetiapine on sleep: A systematic review and meta-analysis of clinical trials. European Neuropsychopharmacology, 67, 22–36.

Liu, H., Zhou, R., Yin, L., Si, N., Yang, C., Huang, C., Wang, R., & Chen, X. (2023). β-asarone prolongs sleep via regulating the level of glutamate in the PVN. Biochemical and Biophysical Research Communications, 665, 71–77.

Liu, W., Wu, B., Shang, J. K., Wang, X., Zhao, Y., & Huang, A. (2022). Moringa oleifera seed ethanol extract and its active component kaempferol potentiate pentobarbital-induced sleeping behaviours in mice via a GABAergic mechanism. Pharmaceutical Biology, 60(1), 810–824.

Lopresti, A. L., Smith, S. J., Ali, S., Metse, A., Kalns, J., & Drummond, P. D. (2021). Effects of a Bacopa monnieri extract (Bacognize®) on stress, fatigue, quality of life and sleep in adults with self-reported poor sleep: A randomised, double-blind, placebo-controlled study. Journal of Functional Foods, 85, 104671.

Louzada, L. L., Machado, F. V., De Tôledo Nóbrega, O., & Camargos, E. F. (2021). Zopiclone to treat insomnia in older adults: A systematic review. European Neuropsychopharmacology, 50, 75–92.

Mang, G. M., Dürst, T., Bürki, H., Imobersteg, S., Abramowski, D., Schuepbach, E., Hoyer, D., Fendt, M., & Gee, C. E. (2012). The dual Orexin receptor antagonist Almorexant induces sleep and decreases Orexin-Induced locomotion by blocking orexin 2 receptors. SLEEP, 35(12), 1625–1635.

Medic, G., Wille, M., & Hemels, M. (2017). Short- and long-term health consequences of sleep disruption. Nature and Science of Sleep, Volume 9, 151–161.

Mieda, M. (2017). The roles of orexins in sleep/wake regulation. Neuroscience Research, 118, 56–65.

Miller, M. A. (2015). The role of sleep and sleep disorders in the development, diagnosis, and management of neurocognitive disorders. Frontiers in Neurology, 6.

Moline, M., Thein, S., Bsharat, M., Rabbee, N., Kemethofer-Waliczky, M., Filippov, G., Naoki, K., & Dhadda, S. (2020). Safety and efficacy of lemborexant in patients with Irregular Sleep-Wake Rhythm Disorder and Alzheimer’s Disease dementia: results from a phase 2 randomized clinical trial. The Journal of Prevention of Alzheimer’s Disease, 1–12.

Nasim, K., Haniyeh, A., Farahnaz, H., Mahdis, N., Shekofe, T., Abolfazl, M.B. (2020). Evaluation of Extract Efficacy of Lemon Balm on Sleep Quality Score in Postmenopausal Women: A Double-Blinded Randomized Clinical Trial. Der. Pharmacia. Lettre. 12(9), 22-29.

National Sleep Foundation. (2021, 12, 3). Sleep by the Numbers. sleep-facts-and-statistics/

Neubauer, D. N. (2008). A review of ramelteon in the treatment of sleep disorders. Neuropsychiatric Disease and Treatment, 69.

Nie, T., & Blair, H. A. (2023). Daridorexant in insomnia Disorder: A Profile of its Use. CNS Drugs, 37(3), 267–274.

Oh, S., Yu, J., Kim, H., Oh, K., & Eun, J. (2011). Effects of white lotus extracts on sleeping, chloride influx, and oxidation. Food Science and Biotechnology, 20(4), 949–954.

Panara, K., Nariya, M., Karra, N. (2020). Central nervous system depressant activity of Jatamansi (Nardostachys jatamansi DC.) rhizome. Ayu. 41(4), 250-254. doi: 10.4103/ayu.AYU_251_20.

Patel, D., Shankar, S., Preeti, B., Basu, S., Deshmukh, G., Datir, R. (2018). Brahmi (Bacopa monnieri) as functional food ingredient in food processing industry. J. Pharmacognosy. Phytochemistry, 7(3), 189-194.

Patel, S., Verma, N.K., Karunakaran, G. (2009). Passiflora Incarnata Linn: A Review on Morphology, Phytochemistry and Pharmacological Aspects. Phcog Rev. 3, 5, 175-181.

Pavlova, M., & Latreille, V. (2019). Sleep disorders. The American Journal of Medicine, 132(3), 292–299.

Pegram, V., Hyde, P., & Linton, P. (1980). Chronic use of triazolam: The effects on the sleep patterns of insomniacs. Journal of International Medical Research, 8(3), 224–231.

Petr, D., Jitka, B., Evzen, R., Veronika, M., Antonin, S., Robert, J., Jan, R., & Karel, S. (2010). Effects of Ropinirole Prolonged-Release on Sleep Disturbances and Daytime Sleepiness in Parkinson Disease. Clinical. Neuropharmacology. 33, 186- 190.

Pierantozzi, M., Placidi, F., Liguori, C., Albanese, M., Imbriani, P., Marciani, M. G., Mercuri, N. B., Stanzione, P., & Stefani, A. (2016). Rotigotine may improve sleep architecture in Parkinson’s disease: a double-blind, randomized, placebo-controlled polysomnographic study. Sleep Medicine, 21, 140–144.

Pizza, F., Barateau, L., Dauvilliers, Y., & Plazzi, G. (2022). The orexin story, sleep and sleep disturbances. Journal of Sleep Research, 31(4).

Roehrs, T., Zorick, F., Lord, N., Koshorek, G.L., & Roth, T. (1983). Dose-related effects of estazolam on sleep of patients with insomnia. J. Clin.Psychopharmacol, 3(3), 152-6. PMID: 6135720.

Saletu, A., Parapatics, S., Saletu, B., Anderer, P., Prause, W., Putz, H., Adelbauer, J., & Saletu-Zyhlarz, G. (2005). On the Pharmacotherapy of Sleep Bruxism: Placebo-Controlled Polysomnographic and Psychometric Studies with Clonazepam. Neuropsychobiology, 51(4), 214–225.

Schmidt, M. H., Koshal, V. B., & Schmidt, H. S. (2006). Use of pramipexole in REM sleep behavior disorder: Results from a case series. Sleep Medicine, 7(5), 418–423.

Sharma, R., Singla, R. K., Banerjee, S., Sinha, B., Shen, B., & Sharma, R. (2022). Role of Shankhpushpi (Convolvulus pluricaulis) in neurological disorders: An umbrella review covering evidence from ethnopharmacology to clinical studies. Neuroscience & Biobehavioral Reviews, 140, 104795.

Sharma, V., Sharma, R., Gautam, D. N. S., Kuča, K., Nepovimová, E., & Martins, N. (2020). Role of Vacha (Acorus calamus Linn.) in Neurological and Metabolic Disorders: Evidence from Ethnopharmacology, Phytochemistry, Pharmacology and Clinical Study. Journal of Clinical Medicine, 9(4), 1176.

Sobhanifar, M., Rashidi, R., Rajabian, A., Forouzanfar, F., Hasanpour, M., Iranshahi, M., Rakhshandeh, H., & Hosseini, A. (2022). The possible mechanism of Datura stramonium on pentobarbital-induced sleep in mice. International Journal of Neuroscience, 133(8), 879–887.

Sun, Y., Tisdale, R. K., & Kilduff, T. S. (2021). Hypocretin/Orexin receptor pharmacology and sleep phases. In Frontiers of neurology and neuroscience (pp. 22–37).

Taheri, S., & Mignot, E. (2002). The genetics of sleep disorders. Lancet Neurology, 1(4), 242–250.

Thakkar, M. (2011). Histamine in the regulation of wakefulness. Sleep Medicine Reviews, 15(1), 65–74.

Toolika, E., Bhat, N. P., & Shetty, S. K. (2015). A comparative clinical study on the effect of Tagara (Valeriana wallichii DC.) and Jatamansi (Nardostachys jatamansi DC.) in the management of Anidra (primary insomnia). Ayu, 36(1), 46.

Tuo, W., Wang, S., Shi, Y., Cao, W., Liu, Y., Su, Y., Xiu, M., & He, J. (2023). Angelica sinensis polysaccharide extends lifespan and ameliorates aging-related diseases via insulin and TOR signaling pathways, and antioxidant ability in Drosophila. International Journal of Biological Macromolecules, 241, 124639.

Unno, K., Noda, S., Kawasaki, Y., Yamada, H., Morita, A., Iguchi, K., & Nakamura, Y. (2017). Reduced Stress and Improved Sleep Quality Caused by Green Tea Are Associated with a Reduced Caffeine Content. Nutrients, 9(7), 777.

Walsh, J. H., Visser, C., Maddison, K. J., Bharat, C., Hillman, D. R., & Eastwood, P. R. (2018). The effect of temazepam on assessment of severity of obstructive sleep apnea by polysomnography. Sleep and Breathing, 23(1), 49–56.

Wichniak, A., Wierzbicka, A., & Jarema, M. (2021). Treatment of insomnia – effect of trazodone and hypnotics on sleep. Psychiatria Polska, 55(4), 743–755.

Winters, B., Serpas, D. G., Fullmer, N., Hughes, K., Kincaid, J., Rosario, E. R., & Schnakers, C. (2023). Sleep quality should be assessed in inpatient rehabilitation settings: a preliminary study. Brain Sciences, 13(5), 718.

Yeung, W., Chung, K. F., Yung, K., & Ng, T. H. (2015). Doxepin for insomnia: A systematic review of randomized placebo-controlled trials. Sleep Medicine Reviews, 19, 75–83.

Yuan, Q., Joiner, W. J., & Sehgal, A. (2006). A Sleep-Promoting role for the drosophila serotonin receptor 1A. Current Biology, 16(11), 1051–1062.


Article Metrics

Abstract views : 1367 | views : 820


  • There are currently no refbacks.

Copyright (c) 2024 Majalah Obat Tradisional

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

©Majalah Obat Tradisional (Traditional Medicine Journal)
 ISSN 2406-9086
Faculty of Pharmacy
Universitas Gadjah Mada