Exploring natural products for insomnia: Effective solutions for better sleep

Abstract

Insomnia, affecting millions worldwide, is a prevalent sleep disorder characterized by persistent difficulties in both initiating and maintaining sleep, leading to compromised daytime functioning, heightened risks of cardiovascular and psychiatric comorbidities, and substantial socioeconomic burdens necessitating the pursuit of safer and more efficacious therapeutic interventions. This review systematically evaluated research studies published between 2020 and 2024 on 71 natural product-based insomnia treatments—classified by chemical structure (terpenoids, flavonoids, and polyphenols)—and investigated their underlying GABAergic, serotonergic, and antioxidative mechanisms using both in vivo and in vitro evidence to elucidate potential multi-target benefits. In sum, although natural products represent a promising avenue for safer multi-faceted insomnia management, additional rigorous clinical studies and integrative methodologies are critical to establish efficacy, delineate molecular mechanisms, and advance these agents toward more precise and sustainable therapeutic applications.

Keywords

insomnia / natural products / plant-derived / sleep

References

[1] Riemann D, Benz F, Dressle RJ, et al. Insomnia disorder: state of the science and challenges for the future. J Sleep Res. 2022; 31(4):e13604. https://doi.org/10.1111/jsr.13604

[2] Ferini-Strambi L, Auer R, Bjorvatn B, et al. Insomnia disorder: clinical and research challenges for the 21st century. Eur J Neurol. 2021; 28(7): 2156-2167. https://doi.org/10.1111/ene.14784

[3] Roach M, Juday T, Tuly R, Chou JW, Jena AB, Doghramji PP. Challenges and opportunities in insomnia disorder. Int J Neurosci. 2021; 131(11): 1058-1065. https://doi.org/10.1080/00207454.2020.1773460

[4] Palagini L, Hertenstein E, Riemann D, Nissen C. Sleep, insomnia and mental health. J Sleep Res. 2022; 31(4):e13628. https://doi.org/10.1111/jsr.13628

[5] Fan MY, Sun DJY, Zhou T, et al. Sleep patterns, genetic susceptibility, and incident cardiovascular disease: a prospective study of 385 292 UK biobank participants. Eur Heart J. 2020; 41(11): 1182-1189. https://doi.org/10.1093/eurheartj/ehz849

[6] Hertenstein E, Trinca E, Wunderlin M, et al. Cognitive behavioral therapy for insomnia in patients with mental disorders and comorbid insomnia: a systematic review and meta-analysis. Sleep Med Rev. 2022; 62:101597. https://doi.org/10.1016/j.smrv.2022.101597

[7] Jupe T, Zenelaj B. Effectiveness of drugs for insomnia treatment. Meeting abstract. Eur Psychiat. 2022; 65(S1): S811-S812. https://doi.org/10.1192/j.eurpsy.2022.2100

[8] Yue JL, Chang XW, Zheng JW, et al. Efficacy and tolerability of pharmacological treatments for insomnia in adults: a systematic review and network meta-analysis. Review. Sleep Med Rev. 2023; 68:101746. https://doi.org/10.1016/j.smrv.2023.101746

[9] Lelli D, Cortese L, Pedone C. Use of plant-derived natural products in sleep disturbances. Adv Exp Med Biol. 2021; 1308: 217-224. https://doi.org/10.1007/978-3-030-64872-5_15

[10] Jiang S, Li H, Zhang L, et al. Generic diagramming platform (GDP): a comprehensive database of high-quality biomedical graphics. Nucleic Acids Res. 2025; 53(D1): D1670-d1676. https://doi.org/10.1093/nar/gkae973

[11] Yang WQ, Chen X, Li YL, Guo SF, Wang Z, Yu XL. Advances in pharmacological activities of terpenoids. Nat Prod Commun. 2020; 15(3):1934578x20903555. https://doi.org/10.1177/1934578x20903555

[12] Shen CY, Wan L, Zhu JJ, Jiang JG. Targets and underlying mechanisms related to the sedative and hypnotic activities of saponin extracts from semen Ziziphus jujube. Food Funct. 2020; 11(5): 3895-3903. https://doi.org/10.1039/d0fo00098a

[13] Yan Y, Shen CX, Pei XP, et al. Compare the chemical profiling of Ziziphi Spinosae Semen and Ziziphi Mauritianae Semen using untargeted metabolomics. J Food Compos Anal. 2020; 94:103635. https://doi.org/10.1016/j.jfca.2020.103635

[14] Yan Y, Liu J, Zhang M, et al. A strategy to explore the quality markers of Ziziphi Spinosae Semen by combining metabolic in vivo study with network pharmacology. Biomed Chromatogr. 2023; 37(1):e5530. https://doi.org/10.1002/bmc.5530

[15] Yao WQ, Zhao YH, Zheng YW, Zhang Q, Han X. Network meta-analysis of Chinese patent medicines of Ziziphi Spinosae Semen in treatment of primary insomnia. Zhongguo Zhong Yao Za Zhi. 2021; 46(17): 4541-4554. https://doi.org/10.19540/j.cnki.cjcmm.20210114.501

[16] Sun M, Li M, Cui X, et al. Terpenoids derived from Semen Ziziphi Spinosae oil enhance sleep by modulating neurotransmitter signaling in mice. Heliyon. 2024; 10(5):e26979. https://doi.org/10.1016/j.heliyon.2024.e26979

[17] Shao J, Zheng X, Qu L, et al. Ginsenoside Rg5/Rk1 ameliorated sleep via regulating the GABAergic/serotoninergic signaling pathway in a rodent model. Food Funct. 2020; 11(2): 1245-1257. https://doi.org/10.1039/c9fo02248a

[18] Xia TJ, Jin SW, Liu YG, et al. Shen Yuan extract exerts a hypnotic effect via the tryptophan/5-hydroxytryptamine/melatonin pathway in mice. J Ethnopharmacol. 2024; 326:117992. https://doi.org/10.1016/j.jep.2024.117992

[19] Manor R, Kumarnsit E, Samerphob N, Rujiralai T, Puangpairote T, Cheaha D. Characterization of pharmaco-EEG fingerprint and sleep-wake profiles of Lavandula angustifolia Mill. essential oil inhalation and diazepam administration in rats. J Ethnopharmacol. 2021; 276:114193. https://doi.org/10.1016/j.jep.2021.114193

[20] Şahin F, Özkaraman A, Irmak Kaya Z. The effect of a combined treatment of foot soak and lavender oil inhalation therapy on the severity of insomnia of patients with cancer: randomized interventional study. Explore. 2023; 19(3): 426-433. https://doi.org/10.1016/j.explore.2022.09.003

[21] Lucena L, Santos-Junior JG, Tufik S, Hachul H. Effect of a lavender essential oil and sleep hygiene protocol on insomnia in postmenopausal women: a pilot randomized clinical trial. Explore. 2024; 20(1): 116-125. https://doi.org/10.1016/j.explore.2023.07.004

[22] Seifritz E, Kasper S, Möller HJ, et al. Effect of anxiolytic drug silexan on sleep - a narrative review. World J Biol Psychiatr. 2022; 23(7): 493-500. https://doi.org/10.1080/15622975.2021.2013092

[23] von Känel R, Kasper S, Bondolfi G, et al. Therapeutic effects of Silexan on somatic symptoms and physical health in patients with anxiety disorders: a meta-analysis. Brain Behav. 2021; 11(4):e01997. https://doi.org/10.1002/brb3.1997

[24] Xu Y, Ma L, Liu F, et al. Lavender essential oil fractions alleviate sleep disorders induced by the combination of anxiety and caffeine in mice. J Ethnopharmacol. 2023; 302(Pt A):115868. https://doi.org/10.1016/j.jep.2022.115868

[25] Hao YF, Luo T, Lu ZY, Shen CY, Jiang JG. Targets and underlying mechanisms related to the sedative and hypnotic activities of saponins from Rhodiola rosea L. (crassulaceae). Food Funct. 2021; 12(21): 10589-10601. https://doi.org/10.1039/d1fo01178b

[26] Wuken S, Li J, Gao X, et al. Zerumbone, a major sesquiterpene from Syringa pinnatifolia Hemsl., exerts the sedative effect by regulating GABAergic nervous system. J Ethnopharmacol. 2023; 301:115813. https://doi.org/10.1016/j.jep.2022.115813

[27] Lopresti AL, Smith SJ, Drummond PD. An investigation into an evening intake of a saffron extract (affron®) on sleep quality, cortisol, and melatonin concentrations in adults with poor sleep: a randomised, double-blind, placebo-controlled, multi-dose study. Sleep Med. 2021; 86: 7-18. https://doi.org/10.1016/j.sleep.2021.08.001

[28] Xu J, Tai B, Jiao S, et al. The ethanol extract of Syringa oblata heartwood, a Mongolian folk medicine containing major lignans, exerts analgesic and sedative effects on mice. Chem Biodivers. 2023; 20(1):e202200984. https://doi.org/10.1002/cbdv.202200984

[29] Qiu Y, Mao ZJ, Ruan YP, Zhang X. Exploration of the anti-insomnia mechanism of Ganoderma by central-peripheral multi-level interaction network analysis. BMC Microbiol. 2021; 21(1):296. https://doi.org/10.1186/s12866-021-02361-5

[30] Li KX, Liu WZ, Wu CH, et al. The anti-fatigue and sleep-aiding effects vary significantly among different recipes containing Ganoderma lucidum extracts. Heliyon. 2024; 10(10):e30907. https://doi.org/10.1016/j.heliyon.2024.e30907

[31] Kim H, Park I, Park K, Park S, Kim YI, Park BG. The positive effects of Poria cocos extract on quality of sleep in Insomnia rat models. Int J Environ Res Public Health. 2022; 19(11):6629. https://doi.org/10.3390/ijerph19116629

[32] Hou W, Feng J, Sun Y, Chen X, Liu Y, Wei J. Utilizing metabolomics and network analysis to explore the effects of artificial production methods on the chemical composition and activity of agarwood. Front Pharmacol. 2024; 15:1357381. https://doi.org/10.3389/fphar.2024.1357381

[33] Dong M, Du H, Li X, et al. Discovery of biomarkers and potential mechanisms of agarwood incense smoke intervention by untargeted metabolomics and network pharmacology. Drug Des Devel Ther. 2022; 16: 265-278. https://doi.org/10.2147/dddt.S348028

[34] Weston-Green K, Clunas H, Naranjo CJ. A review of the potential use of pinene and linalool as terpene-based medicines for brain health: discovering novel therapeutics in the flavours and fragrances of cannabis. Front Psychiatr. 2021; 12:583211. https://doi.org/10.3389/fpsyt.2021.583211

[35] Wen J, Yang Y, Hao J. Acori Tatarinowii Rhizoma: a comprehensive review of its chemical composition, pharmacology, pharmacokinetics and toxicity. Front Pharmacol. 2023; 14:1090526. https://doi.org/10.3389/fphar.2023.1090526

[36] Liu Y, Wang Z, Wang C, et al. Comprehensive phytochemical analysis and sedative-hypnotic activity of two Acanthopanax species leaves. Food Funct. 2021; 12(5): 2292-2311. https://doi.org/10.1039/d0fo02814b

[37] Li Y-M, Shen C-Y, Jiang J-G. Sedative and hypnotic effects of the saponins from a traditional edible plant Liriope spicata Lour. in PCPA-induced insomnia mice. J Ethnopharmacol. 2024; 327:118049. https://doi.org/10.1016/j.jep.2024.118049

[38] Zhang L, Yong Y-Y, Deng L, et al. Therapeutic potential of Polygala saponins in neurological diseases. Phytomedicine. 2023; 108:154483. https://doi.org/10.1016/j.phymed.2022.154483

[39] Li J, Li X, Wang C, Zhang M, Ye M, Wang Q. The potential of Valeriana as a traditional Chinese medicine: traditional clinical applications, bioactivities, and phytochemistry. Front Pharmacol. 2022; 13:973138. https://doi.org/10.3389/fphar.2022.973138

[40] Maurya AK, Agnihotri VK. Valeriana jatamansi: Bioactive compounds and their medicinal uses. Curr Top Med Chem. 2024; 24(9): 757-796. https://doi.org/10.2174/0115680266273617240129042653

[41] Freitas C, Khanal S, Landsberg D, Kaul V. An alternative cause of encephalopathy: valerian root overdose. Cureus. 2021; 13(9):e17759. https://doi.org/10.7759/cureus.17759

[42] Shinjyo N, Waddell G, Green J. Valerian root in treating sleep problems and associated disorders - A systematic review and meta-analysis. J Evid Based Integr Med. 2020; 25:2515690x20967323. https://doi.org/10.1177/2515690x20967323

[43] Ota M, Maki Y, Xu LY, Makino T. Prolonging effects of Valeriana fauriei root extract on pentobarbital-induced sleep in caffeine-induced insomnia model mice and the pharmacokinetics of its active ingredients under conditions of glycerol fatty acid ester as emulsifiers. J Ethnopharmacol. 2022; 298:115625. https://doi.org/10.1016/j.jep.2022.115625

[44] Chandra Shekhar H, Joshua L, Thomas JV. Standardized extract of Valeriana officinalis improves overall sleep quality in human subjects with sleep complaints: a randomized, double-blind, placebo-controlled, clinical study. Adv Ther. 2024; 41(1): 246-261. https://doi.org/10.1007/s12325-023-02708-6

[45] Mohan ME, Mohan MC, Prabhakaran P, Das SS, Krishnakumar IM, Chakrapani PSB. Exploring the short-term influence of a proprietary oil extract of black cumin (Nigella sativa) on non-restorative sleep: a randomized, double-blinded, placebo-controlled actigraphy study. Front Nutr. 2024; 10:101200118. https://doi.org/10.3389/fnut.2023.1200118

[46] Ke QF, Yang JQ, Zhu JC, et al. Effect of Hemerocallis essence aroma on brain activity and sleep processes via scalp electroencephalogram. Flavour Fragrance J. 2024; 39(4): 214-223. https://doi.org/10.1002/ffj.3782

[47] Xiao SS, Liu SY, Yu H, et al. A study on the mechanism of the sedative-hypnotic effect of Cinnamomum camphora chvar. Borneol essential oil based on network pharmacology. J Oleo Sci. 2022; 71(7): 1063-1073. https://doi.org/10.5650/jos.ess21278

[48] Afif Z, Eddy Santoso MI, Khotimah H, et al. Effect of Centella asiatica ethanol extract on zebrafish larvae (Danio rerio) insomnia model through inhibition of Orexin, ERK, Akt and p38. F1000Res. 2024; 13:107. https://doi.org/10.12688/f1000research.141064.1

[49] Luo Y, Zhang Y, Lan K, Zhang Y. The mechanism of lingze tablet in treating prostatitis and insomnia: based on network pharmacology, bioinformatics and molecular docking. Asian J Surg. 2024; 47(7): 3185-3187. https://doi.org/10.1016/j.asjsur.2024.03.039

[50] Tan XH, Wang LP, Smith WK, et al. Aquilaria sinensis leaf tea affects the immune system and increases sleep in zebrafish. Front Pharmacol. 2023; 14:1246761. https://doi.org/10.3389/fphar.2023.1246761

[51] Min B, Ahn Y, Cho H-J, Kwak W-K, Jo K, Suh HJ. (Humulus lupulus L.)Chemical compositions and sleep-promoting activities of hop (Humulus lupulus L.) varieties. J Food Sci. 2023; 88(5): 2217-2228. https://doi.org/10.1111/1750-3841.16544

[52] Langley BO, Ryan JJ, Hanes D, et al. Xanthohumol microbiome and signature in healthy adults (the XMaS trial): safety and tolerability results of a phase I triple-masked, placebo-controlled clinical trial. Mol Nutr Food Res. 2021; 65(8):2001170. https://doi.org/10.1002/mnfr.202001170

[53] Min B, Ahn Y, Cho HJ, Kwak WK, Suh HJ, Jo K. GABA(A) receptor-mediated sleep-promoting effect of Saaz-Saphir hops mixture containing xanthohumol and humulone. Molecules. 2021; 26(23):7108. https://doi.org/10.3390/molecules26237108

[54] Um MY, Yoon M, Lee J, Jung J, Cho S. A novel potent sleep-promoting effect of turmeric: turmeric increases non-rapid eye movement sleep in mice via Histamine H(1)Receptor blockade. Mol Nutr Food Res. 2021; 65(14):e2100100. https://doi.org/10.1002/mnfr.202100100

[55] Um MY, Yoon M, Kim M, et al. Curcuminoids, a major turmeric component, have a sleep-enhancing effect by targeting the histamine H1 receptor. Food Funct. 2022; 13(24): 12697-12706. https://doi.org/10.1039/d2fo02087d

[56] Ahn Y, Kim S, Park C, Kim JE, Suh HJ, Jo K. Sleep-promoting activity of lotus (Nelumbo nucifera) rhizome water extract via GABA(A) receptors. Pharm Biol. 2022; 60(1): 1341-1348. https://doi.org/10.1080/13880209.2022.2096076

[57] Kim S, Hong KB, Jo K, Suh HJ. Quercetin-3-O-glucuronide in the ethanol extract of lotus leaf (Nelumbo nucifera) enhances sleep quantity and quality in a rodent model via a GABAergic mechanism. Molecules. 2021; 26(10):3023. https://doi.org/10.3390/molecules26103023

[58] Sayson LV, Jeon SJ, Ortiz DM, Campomayor NB, Kim HJ, Kim M. Heukharang (Lactuca sativa L.) extracts enhanced the sleep behavior of mice: potential involvement of adenosine A₁ and A_2A receptors. Sleep Biol Rhythms. 2024; 22(3): 385-394. https://doi.org/10.1007/s41105-024-00522-3

[59] Ahn Y, Lee HH, Kim BH, et al. Heukharang lettuce (Lactuca sativa L.) leaf extract displays sleep-promoting effects through GABA(A) receptor. J Ethnopharmacol. 2023; 314:116602. https://doi.org/10.1016/j.jep.2023.116602

[60] Forouzanfar F, Vahedi MM, Aghaei A, Rakhshandeh H. Hydroalcoholic extract of Cuscuta epithymum enhances pentobarbitalinduced sleep: possible involvement of GABAergic system. Curr Drug Discov Technol. 2020; 17(3): 332-337. https://doi.org/10.2174/1570163815666181105091801

[61] Wang L, Wang P, Chen Y, et al. Utilizing network pharmacology and experimental validation to explore the potential molecular mechanisms of BanXia-YiYiRen in treating insomnia. Bioengineered. 2022; 13(2): 3148-3170. https://doi.org/10.1080/21655979.2022.2026862

[62] Ahmad M, Mohammad N, Al-Maswood A, et al. Comparison of antioxidant role of methanol, acetone and water extracts of Andrographis paniculata Nees. J Med Plants Res. 2020; 14(8):2775D0564285. https://doi.org/10.5897/jmpr2020.6999

[63] Lu P, Zhang C, Zheng J, Li C, Zhang Q, Huang B. A comparison review of Hehuan flowers and Hehuan bark on the traditional applications, phytochemistry and pharmacological effects. J Ethnopharmacol. 2023; 303:116002. https://doi.org/10.1016/j.jep.2022.116002

[64] He Y, Wang Q, Ye Y, Liu Z, Sun H. The ethnopharmacology, phytochemistry, pharmacology and toxicology of genus Albizia: a review. J Ethnopharmacol. 2020; 257:112677. https://doi.org/10.1016/j.jep.2020.112677

[65] Guo R, Shi A-M, Deng L, et al. Flavonoid-like components of peanut stem and leaf extract promote sleep by decreasing neuronal excitability. Mol Nutr Food Res. 2022; 66(1):2100210. https://doi.org/10.1002/mnfr.202100210

[66] Quinto-Ortiz YE, Gonzalez-Trujano ME, Sanchez-Jaramillo E, et al. Pharmacological interaction of quercetin derivatives of Tilia americana and clinical drugs in experimental fibromyalgia. Metabolites. 2022; 12(10):916. https://doi.org/10.3390/metabo12100916

[67] Mushtaq Z, Sadeer NB, Hussain M, et al. Therapeutical properties of apigenin: a review on the experimental evidence and basic mechanisms. Int J Food Prop. 2023; 26(1): 1914-1939. https://doi.org/10.1080/10942912.2023.2236329

[68] Abdullah A, Khan WA. Sweet violet (Viola odorata L.) Banafsha a medicinal plant in Himalayan region of Jammu and Kashmir: a review. Pharma Innov. 2023; 12(7): 149-153.

[69] Li S, Chen Y, Duan Y, et al. Widely targeted metabolomics analysis of different parts of Salsola collina Pall. Molecules. 2021; 26(4):1126. https://doi.org/10.3390/molecules26041126

[70] Wang J, Wang H, Yu J, Cui Q, Hou L, Tian J. Diaphragma juglandis fructus-traditional uses, chemical composition, and pharmacological effects of Diaphragma juglandis fructus: a review. J Ethnopharmacol. 2023; 312:116440. https://doi.org/10.1016/j.jep.2023.116440

[71] Kiranmayi GVN, Hema Pushpavathi V. Anxiolytic and hypnotic effects of ethanolic root extract of Carica papaya in mice. Int J Green Pharm. 2020; 14(4): 348-354.

[72] Janda K, Wojtkowska K, Jakubczyk K, Antoniewicz J, Skonieczna-Żydecka K. Passiflora incarnata in neuropsychiatric disorders - A systematic review. Nutrients. 2020; 12(12):3894. https://doi.org/10.3390/nu12123894

[73] Lee J, Jung HY, Lee SI, Choi JH, Kim SG. Effects of Passiflora incarnata Linnaeus on polysomnographic sleep parameters in subjects with insomnia disorder: a double-blind randomized placebo-controlled study. Int Clin Psychopharmacol. 2020; 35(1): 29-35. https://doi.org/10.1097/yic.0000000000000291

[74] Rakhshandeh H, Rashidi R, Vahedi MM, Khorrami MB, Abbassian H, Forouzanfar F. Hypnotic activity of Capparis spinosa hydro-alcoholic extract in mice. Recent Pat Food Nutr Agric. 2021; 12(1): 58-62. https://doi.org/10.2174/2212798411666200727151142

[75] Liu WL, Wu BF, Shang JH, Wang XF, Zhao YL, Huang AX. Moringa oleifera seed ethanol extract and its active component kaempferol potentiate pentobarbital-induced sleeping behaviours in mice via a GABAergic mechanism. Pharm Biol. 2022; 60(1): 810-824. https://doi.org/10.1080/13880209.2022.2056207

[76] Wang CD, Hou XJ, Zhao F, et al. Literature research and traditional Chinese medicine properties of Aspalathus linearis. Zhongguo Zhong Yao Za Zhi. 2021; 46(8): 1960-1966. https://doi.org/10.19540/j.cnki.cjcmm.20200915.410

[77] Liu L, Feng WH, Liu XQ, Liang YH, Li C, Wang ZM. Research progress on Polygalae radix. Zhongguo Zhong Yao Za Zhi. 2021; 46(22): 5744-5759. https://doi.org/10.19540/j.cnki.cjcmm.20210518.601

[78] Hou XJ, Zhao F, Wang CD, et al. Literature research of Passiflora incarnata and discussion of its traditional Chinese medicine properties. Zhongguo Zhong Yao Za Zhi. 2021; 46(8): 1943-1950. https://doi.org/10.19540/j.cnki.cjcmm.20200915.401

[79] Yang K, Qiu J, Huang Z, et al. A comprehensive review of ethnopharmacology, phytochemistry, pharmacology, and pharmacokinetics of Schisandra chinensis (Turcz.) Baill. and Schisandra sphenanthera Rehd. et Wils. J Ethnopharmacol. 2022; 284:114759. https://doi.org/10.1016/j.jep.2021.114759

[80] Adetunji TL, Acho MA, Samuel VO, Ohoro CR, Ramulondi M. Erythrina velutina Willd.: a review of its traditional uses, phytochemistry, pharmacology, and toxicology. J Ethnopharmacol. 2024; 319(Pt 2):117273. https://doi.org/10.1016/j.jep.2023.117273

[81] Chan CB, Poulie CBM, Wismann SS, Soelberg J, Kristensen JL. The Alkaloids from Lophophora diffusa and other “false peyotes”. J Nat Prod. 2021; 84(8): 2398-2407. https://doi.org/10.1021/acs.jnatprod.1c00381

[82] Si Y, Wang L, Lan J, et al. Lilium davidii extract alleviates p-chlorophenylalanine-induced insomnia in rats through modification of the hypothalamic-related neurotransmitters, melatonin and homeostasis of the hypothalamic-pituitary-adrenal axis. Pharm Biol. 2020; 58(1): 915-924. https://doi.org/10.1080/13880209.2020.1812674

[83] Zhang H, Jin L, Zhang JB, Niu T, Guo T, Chang J. Chemical constituents from the bulbs of Lilium davidii var. unicolor and anti-insomnia effect. Fitoterapia. 2022; 161:105252. https://doi.org/10.1016/j.fitote.2022.105252

[84] Miyazaki K, Itoh N, Saiki P, Kuroki Y. Supplementation with Eurycoma longifolia extract modulates diurnal body temperature fluctuation and sleep rhythm in mice. J Nutr Sci Vitaminol. 2022; 68(4): 342-347. https://doi.org/10.3177/jnsv.68.342

[85] Yoon M, Jung J, Kim M, Lee C, Cho S, Um M. Effect of black pepper (Piper nigrum) extract on caffeine-induced sleep disruption and excitation in mice. Nutrients. 2022; 14(11):2249. https://doi.org/10.3390/nu14112249

[86] Gupta P, Tiwari RC, Mittal B, Dikshit M, Sharma VB. Kuchala; a miracle remedy or poison nut - a review. World J Pharm Res. 2022; 11(2): 213-225. https://doi.org/10.20959/wjpr20222-22749

[87] Monadi T, Azadbakht M, Ahmadi A, Chabra A. A comprehensive review on the ethnopharmacology, phytochemistry, pharmacology, and toxicology of the Mandragora genus; from folk medicine to modern medicine. Curr Pharm Des. 2021; 27(34): 3609-3637. https://doi.org/10.2174/1381612827666210203143445

[88] Poulie CBM, Chan CB, Parka A, et al. In vitro and in vivo evaluation of pellotine: a hypnotic Lophophora alkaloid. ACS Pharmacol Transl Sci. 2023; 6(10): 1492-1507. https://doi.org/10.1021/acsptsci.3c00142

[89] Zheng Q, Mu X, Pan S, Luan R, Zhao P. Ephedrae herba: a comprehensive review of its traditional uses, phytochemistry, pharmacology, and toxicology. J Ethnopharmacol. 2023; 307:116153. https://doi.org/10.1016/j.jep.2023.116153

[90] Bi F, Wang Z, Guo Y, Xia M, Zhu X, Qiao W. A combination of magnoflorine and spinosin improves the antidepressant effects on CUMS mouse model. Curr Drug Metab. 2024; 25(1): 71-80. https://doi.org/10.2174/0113892002284230240213064248

[91] Cheng HB, Liu X, Shang HY, et al. Therapeutic effect of Ziziphi Spinosae Semen extracts on chronic unpredictable mild stress-induced depression and insomnia-like behavior in mice. Zhongguo Zhong Yao Za Zhi. 2025; 50(7): 1817-1829. https://doi.org/10.19540/j.cnki.cjcmm.20241210.401

[92] Sobhanifar MA, Rashidi R, Rajabian A, et al. The possible mechanism of Datura stramonium on pentobarbital-induced sleep in mice. Int J Neurosci. 2023; 133(8): 879-887. https://doi.org/10.1080/00207454.2021.1998045

[93] Ayipo YO, Alananzeh WA, Ahmad I, Patel H, Mordi MN. Structural modelling and in silico pharmacology of β-carboline alkaloids as potent 5-HT1A receptor antagonists and reuptake inhibitors. J Biomol Struct Dyn. 2023; 41(13): 6219-6235. https://doi.org/10.1080/07391102.2022.2104376

[94] He J, Fang J, Wang Y, Ge C, Liu S, Jiang Y. Discovery of small-molecule antagonists of orexin 1/2 receptors from traditional Chinese medicinal plants with a hypnotic effect. Pharmaceuticals. 2023; 16(4):542. https://doi.org/10.3390/ph16040542

[95] Kalam MA, Majeed S. Asrawl - Rauwolfia serpentina (L) Benth. ex. Kurz, an effective drug of Unani system of medicine for neurological and cardiological disorders: a review. World J Pharm Pharm Sci. 2020; 9(3): 915-925. https://doi.org/10.20959/wjpps20202-15674

[96] Li L, Lu JJ, Wang WT, et al. Potential targets of Euodiae Fructus in treatment of insomnia based on network pharmacology. Zhongguo Zhong Yao Za Zhi. 2021; 46(12): 3016-3023. https://doi.org/10.19540/j.cnki.cjcmm.20210419.401

[97] Wicinski M, Fajkiel-Madajczyk A, Kurant Z, et al. Can ashwagandha benefit the endocrine system? A review. Int J Mol Sci. 2023; 24(22):16513. https://doi.org/10.3390/ijms242216513

[98] Cheah KL, Norhayati MN, Husniati Yaacob L, Abdul Rahman R. Effect of Ashwagandha (Withania somnifera) extract on sleep: a systematic review and meta-analysis. PLoS One. 2021; 16(9):e0257843. https://doi.org/10.1371/journal.pone.0257843

[99] Park CW, Hong KB, Suh HJ, Ahn Y. Sleep-promoting activity of amylase-treated Ashwagandha (Withania somnifera L. Dunal) root extract via GABA receptors. J Food Drug Anal. 2023; 31(2): 278-288. https://doi.org/10.38212/2224-6614.3456

[100] Epperson CN, Rubinow DR, Meltzer-Brody S, et al. Effect of brexanolone on depressive symptoms, anxiety, and insomnia in women with postpartum depression: pooled analyses from 3 double-blind, randomized, placebo-controlled clinical trials in the HUMMINGBIRD clinical program. J Affective Disord. 2023; 320: 353-359. https://doi.org/10.1016/j.jad.2022.09.143

[101] Morssinkhof MWL, van Wylick DW, Priester-Vink S, et al. Associations between sex hormones, sleep problems and depression: a systematic review. Neurosci Biobehav Rev. 2020; 118: 669-680. https://doi.org/10.1016/j.neubiorev.2020.08.006

[102] Morssinkhof MWL, Wiepjes CM, Bosman BW, et al. Sex hormones, insomnia, and sleep quality: subjective sleep in the first year of hormone use in transgender persons. Sleep Med. 2023; 107: 316-326. https://doi.org/10.1016/j.sleep.2023.04.028

[103] Bhat NG, Patil KG, Sonawane YP, Jain SC. Pharmacognostical and phytochemical screening of Withania coagulans L. dunal. World J Pharm Pharm Sci. 2023; 12(4): 1535-1551. https://doi.org/10.20959/wjpps20234-24472

[104] Zhang J, Yan X, Tian Y, et al. Synthesis of a new water-soluble melatonin derivative with low toxicity and a strong effect on sleep aid. ACS Omega. 2020; 5(12): 6494-6499. https://doi.org/10.1021/acsomega.9b04120

[105] Ritwiset A, Khajonrit J, Krongsuk S, Maensiri S. Molecular insight on the formation structure and dynamics of melatonin in an aqueous solution and at the water-air interface: a molecular dynamics study. J Mol Graph Modell. 2021; 108:107983. https://doi.org/10.1016/j.jmgm.2021.107983

[106] Stoianovici R, Brunetti L, Adams CD. Comparison of melatonin and zolpidem for sleep in an academic community hospital: an analysis of patient perception and inpatient outcomes. J Pharm Pract. 2021; 34(1): 44-50. https://doi.org/10.1177/0897190019851888

[107] Kamruzzaman ASM, Hiragaki S, Watari Y, et al. Clock-controlled arylalkylamine N-acetyltransferase (aaNAT) regulates circadian rhythms of locomotor activity in the American cockroach, Periplaneta americana, via melatonin/MT2-like receptor. J Pineal Res. 2021; 71(2):e12751. https://doi.org/10.1111/jpi.12751

[108] Ivanova N, Nenchovska Z, Atanasova M, Laudon M, Mitreva R, Tchekalarova J. Chronic piromelatine treatment alleviates anxiety, depressive responses and abnormal hypothalamic-pituitary-adrenal axis activity in prenatally stressed male and female rats. Cell Mol Neurobiol. 2022; 42(7): 2257-2272. https://doi.org/10.1007/s10571-021-01100-8

[109] You C, Yan S, Li M, et al. Fabrication of uniform melatonin microparticles potentially for nasal delivery: a comparison of spray drying and spray freeze drying. Pharm Res. 2024; 41(10): 2057-2073. https://doi.org/10.1007/s11095-024-03770-7

[110] Osadchuk MA, Vasilieva IN, Mironova ED, Korzhenkov NP, Trushin MV. N-[2-(5-methoxy-1H-indole-3-yl)ethyl]acetamide may correct arterial hypertension in people with sleep problems. Acta Fac Med Naissensis. 2023; 40(1): 54-68. https://doi.org/10.5937/afmnai40-37183

[111] Dehnavi P, Rakhshandeh H, Bakhtiari E, Asadpour H, Moshirian Farahi SM, Forouzanfar F. Effect of tomato (Solanum lycopersicum) extract in patients with primary insomnia: a double-blind randomized study. Cent Nerv Syst Agents Med Chem. 2023; 23(2): 137-143. https://doi.org/10.2174/1871524923666230720155754

[112] Hong M, Zhang R, Liu Y, Wu Z, Weng P. The interaction effect between tea polyphenols and intestinal microbiota: role in ameliorating neurological diseases. J Food Biochem. 2022; 46(3):e13870. https://doi.org/10.1111/jfbc.13870

[113] Jahani R, Behzad S, Saffariha M, Toufan Tabrizi N, Faizi M. Sedative-hypnotic, anxiolytic and possible side effects of Salvia limbata C. A. Mey. Extracts and the effects of phenological stage and altitude on the rosmarinic acid content. J Ethnopharmacol. 2022; 282:114630. https://doi.org/10.1016/j.jep.2021.114630

[114] Pérez-Piñero S, Muñoz-Carrillo JC, Echepare-Taberna J, et al. Dietary supplementation with an extract of Aloysia citrodora (Lemon verbena) improves sleep quality in healthy subjects: a randomized double-blind controlled study. Nutrients. 2024; 16(10):1523. https://doi.org/10.3390/nu16101523

[115] Buccato DG, Ullah H, De Lellis LF, et al. In vitro assessment of cortisol release inhibition, bioaccessibility and bioavailability of a chemically characterized Scutellaria lateriflora L. Hydroethanolic extract. Molecules. 2024; 29(3):586. https://doi.org/10.3390/molecules29030586

[116] Kim S, Kim D, Um MY, et al. Marine polyphenol phlorotannins as a natural sleep aid for treatment of insomnia: a review of sedative-hypnotic effects and mechanism of action. Mar Drugs. 2022; 20(12):774. https://doi.org/10.3390/md20120774

[117] Kwon S, Jung JH, Cho S, Moon K-D, Lee J. Dieckol is a natural positive allosteric modulator of GABAA-benzodiazepine receptors and enhances inhibitory synaptic activity in cultured neurons. Nutr Neurosci. 2021; 24(11): 835-842. https://doi.org/10.1080/1028415x.2019.1681089

[118] Miranda AR, Cortez MV, Scotta AV, Rivadero L, Serra SV, Soria EA. Memory enhancement in Argentinian women during postpartum by the dietary intake of lignans and anthocyanins. Nutr Res. 2021; 85: 1-13. https://doi.org/10.1016/j.nutres.2020.10.006

[119] Muchtaridi M, Lestari D, Ikram NKK, Gazzali AM, Hariono M, Wahab HA. Decaffeination and neuraminidase inhibitory activity of Arabica green coffee (Coffea arabica) beans: chlorogenic acid as a potential bioactive compound. Molecules. 2021; 26(11):3402. https://doi.org/10.3390/molecules26113402

[120] Ulgen C, Yildirim AB, Sahin G, Turker AU. Do magnetic field applications affect in vitro regeneration, growth, phenolic profiles, antioxidant potential and defense enzyme activities (SOD, CAT and PAL) in lemon balm (Melissa officinalis L.). Ind Crops Prod. 2021; 169:113624. https://doi.org/10.1016/j.indcrop.2021.113624

[121] Lin TF, Qiu JN, Zhang S, et al. Screening out the anti-insomnia components from Prunella vulgaris L. based on plasma pharmacochemistry combined with pharmacodynamic experiments and UPLC-MS/MS analysis. J Ethnopharmacol. 2021; 279:114373. https://doi.org/10.1016/j.jep.2021.114373

[122] Lagariya L, Soni K, Shah JS. Antitumor effects of polyphenol-rich extract of Euphoria longana seed by vascular endothelial growth factor and transforming growth factor-beta signaling inhibition in experimentally induced oral cancer in rats. Indian J Pharmacol. 2022; 54(5): 329-337. https://doi.org/10.4103/ijp.ijp_802_21

[123] Mottaghipisheh J, Dehsheikh AB, Sourestani MM, Kiss T, Hohmann J, Csupor D. Rare plants with promising phytochemical and pharmacological characteristics: an updated review. Pharmaceuticals. 2020; 13(8):175. https://doi.org/10.3390/ph13080175

[124] Zhou C, Hu Y-F, Zhang Y, et al. Prunella vulgaris L-study on chemical characterization and sleep-improvement function of Prunella vulgaris L. based on the functional components. Food Res Int. 2024; 192:114737. https://doi.org/10.1016/j.foodres.2024.114737

[125] Wojtunik-Kulesza K, Rudkowska M, Kasprzak-Drozd K, Oniszczuk A, Borowicz-Reutt K. Activity of selected group of monoterpenes in Alzheimer's disease symptoms in experimental model studies - a non-systematic review. Int J Mol Sci. 2021; 22(14):7366. https://doi.org/10.3390/ijms22147366

[126] Taherzadeh Z, Khaluyan H, Iranshahy M, Rezaeitalab F, Eshaghi Ghalibaf MH, Javadi B. Evaluation of sedative effects of an intranasal dosage form containing saffron, lettuce seeds and sweet violet in primary chronic insomnia: a randomized, double-dummy, double-blind placebo controlled clinical trial. J Ethnopharmacol. 2020; 262:113116. https://doi.org/10.1016/j.jep.2020.113116

[127] Luo H, Sun SJ, Wang Y, Wang YL. Revealing the sedative-hypnotic effect of the extracts of herb pair Semen Ziziphi Spinosae and Radix Polygalae and related mechanisms through experiments and metabolomics approach. BMC Complement Med Ther. 2020; 20(1):206. https://doi.org/10.1186/s12906-020-03000-8

[128] Nose M, Kobayashi R, Tada M, et al. Comparison of ephedrine and pseudoephedrine contents in 34 Kampo extracts containing Ephedrae Herba used clinically in Japan. J Nat Med. 2023; 77(3): 476-488. https://doi.org/10.1007/s11418-023-01687-w

[129] Khalil HMA, Eliwa HA, El-Shiekh RA, et al. Ashwagandha (Withania somnifera) root extract attenuates hepatic and cognitive deficits in thioacetamide-induced rat model of hepatic encephalopathy via induction of Nrf2/HO-1 and mitigation of NF-κB/MAPK signaling pathways. J Ethnopharmacol. 2021; 277:114141. https://doi.org/10.1016/j.jep.2021.114141

[130] Palmieri G, Vadalà M, Corazzari V, Palmieri B. Insomnia treatment: a new multitasking natural compound based on melatonin and cannabis extracts. Clin Ter. 2022; 173(1): 91-96. https://doi.org/10.7417/ct.2022.2399

RIGHTS & PERMISSIONS

2025 The Author(s). Sleep Research published by John Wiley & Sons Australia, Ltd on behalf of Chinese Sleep Research Society.