Commonly used hypnotics are not very effective for the management of chronic insomnia as they produce several unpleasant side effects. According to a recent report, short-term administration of 10 mg/kg α-Asarone, an active principle of Acorus species, used in traditional Indian and Chinese medicine for a prolonged period without any ill-effects, promoted sleep in rats. However, the efficacy of α-Asarone in promoting sleep on long-term use has not been studied. Study was conducted on four groups of rats, with electrodes implanted for recording sleep. Thermocouple and radio-transmitter were implanted for recording temperatures from hypothalamus and peritoneum. Of these, three groups of rats were sleep deprived for 5 h (9:00–14:00 h) for 21 days after drug (α-Asarone or midozolam) or vehicle administration. The anxiety levels were also studied in these rats. Another group, that received α-Asarone for 21 days, was not subjected to sleep deprivation. Long-term administration of α-Asarone improved both the quantity and quality of NREM sleep, not only in comparison to the vehicle, but also in contrast to midazolam. Moreover, there was no withdrawal effect after stopping the daily administration of α-Asarone for 3 weeks. Anxiety alleviation produced by α-Asarone was better than midazolam. α-Asarone-mediated anxiolysis, mild hypothermia, and NREM sleep-related alterations in temperatures, and its known antioxidant property, might have contributed towards the improvement in NREM sleep and maintenance of REM sleep. The study provides strong pre-clinical evidences for further research on α-Asarone as a possible treatment option for chronic insomnia.
This is a preview of subscription content, log in to check access.
The work was supported by the research grant from the Council of Scientific and Industrial Research, New Delhi, India (CSIR Sanction No: 37(1543)/12-EMR II). AR was supported by CSIR Junior Research Fellowship.
Compliance with ethical standards
Conflict of interest
None of the authors has any financial interest or conflicts of interest related to this work.
All the surgeries and procedures employed in this study were approved by the Institutional Animal Ethics Committee of the Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala (SCT/TAEC-019/June/2012/77).
Wistar rats were obtained from the Division of Laboratory Animal Sciences, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala.
Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev. 2002;6:97–111.CrossRefGoogle Scholar
Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders: an opportunity for prevention? JAMA. 1989;262:1479–84.CrossRefGoogle Scholar
Shapiro CM, Devins GM, Hussain M. ABC of sleep disorders. Sleep problems in patients with medical illness. BMJ. 1993;306:1532.CrossRefGoogle Scholar
Taylor DJ, Mallory LJ, Lichstein KL, et al. Comorbidity of chronic insomnia with medical problems. Sleep. 2007;30:213.CrossRefGoogle Scholar
Chouinard G. Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry. 2004;65:7–12.Google Scholar
Stone JR, Zorick TS, Tsuang J. Dose-related illusions and hallucinations with zaleplon. Clin Toxicol. 2008;46:344–5.CrossRefGoogle Scholar
Herings RM, Stricker BHC, de Boer A, et al. Benzodiazepines and the risk of falling leading to femur fractures: dosage more important than elimination half-life. Arch Intern Med. 1995;155:1801–7.CrossRefGoogle Scholar
Serfaty M, Masterton G. Fatal poisonings attributed to benzodiazepines in Britain during the 1980s. Br J Psychiatry. 1993;163:386–93.CrossRefGoogle Scholar
Alvaro PK, Roberts RM, Harris JK. A systematic review assessing bidirectionality between sleep disturbances, anxiety, and depression. Sleep. 2013;36(7):1059–68.CrossRefGoogle Scholar
Taylor DJ, Lichstein KL, Durrence HH, et al. Epidemiology of insomnia, depression, and anxiety. Sleep. 2005;28(11):1457–64.CrossRefGoogle Scholar
Gulia KK, Radhakrishnan A, Kumar VM. Approach to sleep disorders in the traditional school of Indian medicine. Complementary and alternative medicine. In: Chokroverty S, editor. Sleep disorders medicine part 2, 4th ed. New York: Springer Science + Business Media, LLC; 2017.Google Scholar
Paxino G, Watson C. The rat brain in stereotaxic coordinates. 3rd ed. San Diego: Academic Press, Inc.; 1997.Google Scholar
Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. JCSM. 2008;4:487.PubMedGoogle Scholar
Michelini S, Cassano GB, Frare F, et al. Long-term use of benzodiazepines: tolerance, dependence and clinical problems in anxiety and mood disorders. Pharmacopsychiatry. 1996;29(4):127–34.CrossRefGoogle Scholar
Sanger DJ, Zivkovic B. Investigation of the development of tolerance to the actions of zolpidem and midazolam. Neuropharmacology. 1987;26(10):1513–8.CrossRefGoogle Scholar
Soldatos CR, Dikeos DG, Whitehead A. Tolerance and rebound insomnia with rapidly eliminated hypnotics: a meta-analysis of sleep laboratory studies. Int Clin Psychopharmacol. 1999;14(5):287–304.CrossRefGoogle Scholar
Merica H, Blois R, Gaillard JM. Spectral characteristics of sleep EEG in chronic insomnia. Eur J Neurosci. 1998;10(5):1826–34.CrossRefGoogle Scholar
Aeschbach D, Dijk DJ, Trachel L, et al. Dynamics of slow wave activity and spindle frequency activity in the human sleep EEG: effect of midazolam and zopiclone. Neuropsychopharmacology. 1994;11:237–44.CrossRefGoogle Scholar
Bastian CH, LeBlanc M, Carrier J, et al. Sleep EEG power spectra, insomnia, and chronic use of benzodiazepines. Sleep. 2003;26:313–7.CrossRefGoogle Scholar
Borbely AA, Achermann P. Ultradian dynamics of sleep after a single dose of benzodiazepine hypnotics. Eur J Pharmacol. 1991;195:11–8.CrossRefGoogle Scholar
Feige B, Voderholzer U, Riemann D, et al. Independent sleep EEG slow-wave and spindle band dynamics associated with 4 weeks of continuous application of short-half-life hypnotics in healthy subjects. Clin Neurophysiol. 1999;110:1965–74.CrossRefGoogle Scholar
Kales A, Scharf MB, Kales JD. Rebound insomnia. A potential hazard following withdrawal of certain benzodiazepines. JAMA. 1979;241:1692–5.CrossRefGoogle Scholar
Deboer T, Franken P, Tobler L. Sleep and cortical temperature in the Djungarian hamster under baseline conditions and after sleep deprivation. J Comp Physiol. 1994;174:145–55.CrossRefGoogle Scholar
Parmeggiani PL, Velluti RA. The physiologic nature of sleep. World Sci. 2005;18:391.Google Scholar
Gilbert SS, van den Heuvel CJ, Ferguson SA, et al. Thermoregulation as a sleep signalling system. Sleep Med Rev. 2004;8:81–93.CrossRefGoogle Scholar
Amici R, Bastianini S, Berteotti C, et al. Sleep and bodily functions: the physiological interplay between body homeostasis and sleep homeostasis. Arch Ital Biol. 2014;152:66–78.PubMedGoogle Scholar
Neckelmann D, Mykletun A, Dahl AA. Chronic insomnia as a risk factor for developing anxiety and depression. Sleep. 2007;30(7):873–80.CrossRefGoogle Scholar
Ohayon MM, Roth T. Place of chronic insomnia in the course of depressive and anxiety disorders. J Psychiatr Res. 2003;37(1):9–15.CrossRefGoogle Scholar
Anseloni VZ, Brandao ML. Ethopharmacological analysis of behaviour of rats using variations of the elevated plus-maze. Behav Pharmacol. 1997;8:533–40.CrossRefGoogle Scholar
Zangrossi H, Viana MB, Graeff FG. Anxiolytic effect of intra-amygdala injection of midazolam and 8-hydroxy-2-(di-n-propylamino) tetralin in the elevated T-maze. Eur J Pharmacol. 1999;369:267–70.CrossRefGoogle Scholar
Groenink L, Vinkers C, Oorschot R, et al. Models of anxiety: stress-induced hyperthermia (SIH) in singly housed mice. Curr Protoc Pharmacol. 2009;5:16.PubMedGoogle Scholar
Olivier B, Zethof T, Pattij T, et al. Stress-induced hyperthermia and anxiety: pharmacological validation. Eur J Pharmacol. 2003;463:117–32.CrossRefGoogle Scholar
Borbely AA, Neuhaus HU. Sleep-deprivation: effects on sleep and EEG in the rat. J Comp Physiol. 1979;133(1):71–87.CrossRefGoogle Scholar
Colavito V, Fabene PF, Grassi Zucconi G, et al. Experimental sleep deprivation as a tool to test memory deficits in rodents. Front Syst Neurosci. 2013;7:106.CrossRefGoogle Scholar
Shido O, Sugimoto N, Sakurada S, et al. Body core temperature of rats subjected to daily exercise limited to a fixed time. Int J Biometeorol. 1997;40(3):135–40.CrossRefGoogle Scholar