Insomnia is a very common disorder with significant long-term health consequences. In Australia, 13-33% of the adult population have regular difficulty either getting to sleep, staying asleep, or having good sleep quality1. Chronic insomnia can adversely affect health, quality of life and academic performance. It can increase the risk of motor vehicle accidents, decrease work productivity, contribute to irritability, and increase daytime sleepiness. Insomnia is also considered a contributing risk factor for cardiovascular diseases, chronic pain syndrome, depression, anxiety, diabetes, obesity, and asthma2. Insomnia doubles the risk of future development of depression3, and insomnia symptoms together with shortened sleep are associated with hypertension4.
Acute or short-term insomnia may be caused by stress or changes in schedule or environment and can last for a few days or weeks. On the other hand, chronic insomnia occurs three or more nights a week and lasts more than three months2. Contributing risk factors for insomnia include advancing age, family history and genetics, occupation (shift work, travelling), sleep environment (inadequate light/noise/temperature), lifestyle (irregular sleep schedule, long daytime naps, little physical activity, use of caffeine/nicotine/alcohol/illegal drugs, use of electronic devices close to bedtime, life stressors, hormonal changes, side effects of medication, and concurrent health conditions (depression, anxiety, chronic pain, PTSD, GERD, respiratory issues)2, 5.
The physiological factors that control the sleep-wake cycle include wake-promoting chemicals such as orexin, catecholamine and histamine, and sleep promoting chemicals like GABA, serotonin, adenosine, melatonin and prostaglandin D22. For example, orexin increases neuronal firing in the wake-promoting area of the brain and inhibits the sleep-promoting area6.
Standard therapies for insomnia
Acute and chronic insomnia require different management strategies. Treatment for acute insomnia focuses on avoiding or withdrawing the trigger. Sometimes this is accompanied by the short-term prescription of a benzodiazepine7.
First-line treatment for chronic insomnia includes non-pharmacological therapies, and when needed, pharmacological treatments. Non-pharmacological treatments include cognitive behavioural therapy (CBT) which is considered to be the gold standard, mindfulness, education, sleep restriction therapy, stimulus control, relaxation, and bright light exposure. Pharmacological treatments, when needed to enhance CBT, should be used for less than 5 weeks if possible8 and include benzodiazepine receptor agonists which act on GABA (e.g. zopiclone), valerian, melatonin, orexin receptor antagonists (e.g. suvorexant), antidepressants which act on histamine (e.g. doxepin, mirtazapine, amitriptyline), antipsychotics which act on histamine and serotonin (e.g. olanzapine, quetiapine), and anticonvulsants (e.g. gabapentin, pregabalin)2, 9.
New and potential therapies for insomnia
CBT is the first-line treatment for insomnia, but there is a critical lack of behavioural health providers trained in CBT due lack of training availability and costs. Recent studies have been assessing the effectiveness of digital platforms to deliver training courses to professionals10 and CBT programs to patients11-13.
Lemborexant is an orexin inhibitor that was approved in the US in late December 2019 for the treatment of insomnia characterised by difficulties with sleep onset and/or sleep maintenance in adults14. In clinical trials, lemborexant significantly improved objective and subjective measures of sleep onset and sleep maintenance compared with placebo15, 16. Other orexin inhibitors in late stage clinical trials overseas include daridorexant (nemorexant) and seltorexant14.
Cannabinoids, including the two main plant cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are being increasingly investigated as potential pharmacological interventions for sleep disorders, including insomnia. THC and CBD signal through the endocannabinoid system (ECS) in the brain to regulate anxiety, mood, autonomic function, and the sleep/wake cycle, including the maintenance and promotion of sleep17. Endocannabinoids normally produced in the body play a prominent role in sleep and sleep neurophysiology, and plant cannabinoids can alter these processes18-20. Specifically, the ECS may link circadian regulation systems and the behavioural and physiological processes that are affected, including sleep21. The role of the ECS on circadian rhythms has been further supported by work in animals demonstrating that a lack of normal sleep causes dysregulation within the ECS21, 22, while boosting the ECS at the receptor level is involved in the homeostatic recovery of sleep after non-normal sleep21.
Recent systematic reviews on animal and human studies have found insufficient evidence to support routine clinical use of cannabinoid therapies for the treatment of sleep disorders, but promising preliminary evidence to support further evaluation in randomised controlled trials23, 24. A current Australian clinical trial led by the University of Sydney and the University of NSW, is the first study to use novel assessment techniques including high-density electroencephalography (EEG) with structural brain magnetic resonance imaging (MRI) to examine and localise differences in brain activation during sleep and wake periods in participants with insomnia after treatment with a THC+CBD formulation25. A number of other studies in Australia are investigating the effectiveness of different cannabinoid-based medicines in insomnia (ACTRN12620000741987, ACTRN12620000220965,ACTRN12618000078257). Studies such as these will provide much-needed data on the safety and efficacy of cannabinoids for the treatment of insomnia.
- Cunnington D, Junge MF, Fernando AT. Insomnia: prevalence, consequences and effective treatment. Med J Aust. 2013;199(8):S36-40.
- Kaur H, Spurling BC, Bollu PC. Chronic Insomnia.StatPearls. Treasure Island (FL): StatPearls Publishing. Copyright © 2020, StatPearls Publishing LLC.; 2020.
- Baglioni C, Battagliese G, Feige B, Spiegelhalder K, Nissen C, Voderholzer U, et al. Insomnia as a predictor of depression: a meta-analytic evaluation of longitudinal epidemiological studies. J Affect Disord. 2011;135(1-3):10-9.
- Vozoris NT. The relationship between insomnia symptoms and hypertension using United States population-level data. J Hypertens. 2013;31(4):663-71.
- Insomnia: National Institutes of Health USA; 2021 [Available from: https://www.nhlbi.nih.gov/health-topics/insomnia].
- Levenson JC, Kay DB, Buysse DJ. The pathophysiology of insomnia. Chest. 2015;147(4):1179-92.
- Charles J, Harrison C, Britt H. Insomnia. Aust Fam Physician. 2009;38(5):283.
- Willard AF, Ferris AH. Solving the Problem of Insomnia in Clinical Practice. Med Clin North Am. 2021;105(1):107-16.
- Madari S, Golebiowski R, Mansukhani MP, Kolla BP. Pharmacological Management of Insomnia. Neurotherapeutics. 2021.
- Taylor DJ, Dietch JR, Pruiksma K, Calhoun CD, Milanak ME, Wardle-Pinkston S, et al. Developing and Testing a Web-Based Provider Training for Cognitive Behavioral Therapy of Insomnia. Mil Med. 2021;186(Suppl 1):230-8.
- Godzik C, Crawford S, Ryan E. Feasibility of an online cognitive behavioral therapy program to improve insomnia, mood, and quality of life in bereaved adults ages 55 and older. Geriatr Nurs. 2020;42(1):99-106.
- van der Zweerde T, Lancee J, Ida Luik A, van Straten A. Internet-Delivered Cognitive Behavioral Therapy for Insomnia: Tailoring Cognitive Behavioral Therapy for Insomnia for Patients with Chronic Insomnia. Sleep Med Clin. 2020;15(2):117-31.
- Germain A, Markwald RR, King E, Bramoweth AD, Wolfson M, Seda G, et al. Enhancing behavioral sleep care with digital technology: study protocol for a hybrid type 3 implementation-effectiveness randomized trial. Trials. 2021;22(1):46.
- Liu MT. Current and emerging therapies for insomnia. Am J Manag Care. 2020;26(4 Suppl):S85-s90.
- Kärppä M, Yardley J, Pinner K, Filippov G, Zammit G, Moline M, et al. Long-term efficacy and tolerability of lemborexant compared with placebo in adults with insomnia disorder: results from the phase 3 randomized clinical trial SUNRISE 2. Sleep. 2020;43(9).
- Rosenberg R, Murphy P, Zammit G, Mayleben D, Kumar D, Dhadda S, et al. Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial. JAMA Netw Open. 2019;2(12):e1918254.
- Babson KA, Sottile J, Morabito D. Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr Psychiatry Rep. 2017;19(4):23.
- Kesner AJ, Lovinger DM. Cannabinoids, Endocannabinoids and Sleep. Front Mol Neurosci. 2020;13:125.
- Murillo-Rodriguez E, Budde H, Veras AB, Rocha NB, Telles-Correia D, Monteiro D, et al. The Endocannabinoid System May Modulate Sleep Disorders In Aging. Curr Neuropharmacol. 2019.
- Lafaye G, Desterke C, Marulaz L, Benyamina A. Cannabidiol affects circadian clock core complex and its regulation in microglia cells. Addict Biol. 2019;24(5):921-34.
- Vaughn LK, Denning G, Stuhr KL, de Wit H, Hill MN, Hillard CJ. Endocannabinoid signalling: has it got rhythm? Br J Pharmacol. 2010;160(3):530-43.
- Sanford AE, Castillo E, Gannon RL. Cannabinoids and hamster circadian activity rhythms. Brain Res. 2008;1222:141-8.
- Suraev AS, Marshall NS, Vandrey R, McCartney D, Benson MJ, McGregor IS, et al. Cannabinoid therapies in the management of sleep disorders: A systematic review of preclinical and clinical studies. Sleep Med Rev. 2020;53:101339.
- Bhagavan C, Kung S, Doppen M, John M, Vakalalabure I, Oldfield K, et al. Cannabinoids in the Treatment of Insomnia Disorder: A Systematic Review and Meta-Analysis. CNS Drugs. 2020.
- Suraev A, Grunstein RR, Marshall NS, D’Rozario AL, Gordon CJ, Bartlett DJ, et al. Cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC) for chronic insomnia disorder (‘CANSLEEP’ trial): protocol for a randomised, placebo-controlled, double-blinded, proof-of-concept trial. BMJ Open. 2020;10(5):e034421.