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Cannabinoids in the Treatment of Insomnia Disorder: A Systematic Review and Meta-Analysis

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Abstract

Background

Insomnia is associated with significant comorbidity, disability and impact on quality of life and, despite advances in pharmacotherapy and psychotherapy, remains a significant burden to society. Cannabinoids are gaining acceptance for use as medicines in the treatment of insomnia disorder.

Objective

We conducted a systematic review and meta-analysis to evaluate the efficacy of cannabinoids in the treatment of insomnia disorder.

Methods

We performed a systematic review of the PubMed, Cochrane Library, MEDLINE, and Cumulative Index to Nursing and Allied Health Literature Complete databases from inception to 5 December 2019, and again prior to data abstraction, for studies of cannabis-based products for the treatment of insomnia disorder in adults. Inclusion criteria were (1) clinical studies, (2) participants aged ≥ 18 years, (3) insomnia disorder either formally diagnosed against contemporaneous diagnostic criteria or quantified with validated instruments and (4) compared cannabis-based products with the standard of care, placebo or a sedative. No language restrictions were imposed. Non-primary research, animal studies and studies of cannabis-induced insomnia were excluded. Risk of bias was assessed using the RoB 2 tool for randomised controlled trials (RCTs) and Risk of Bias in Non-randomized Studies—of Interventions (ROBINS-I) tool for non-randomized trials. Heterogeneity was assessed with the I2 statistic.

Results

A total of five studies (two RCTs and three non-randomised studies) with 219 study participants were included, of which three could be combined. The three non-randomised studies contributed data on the Pittsburgh Sleep Quality Index Questionnaire score, showing a favourable effect of cannabinoids at ≤ 4 weeks of follow-up (mean difference − 1.89 [95% confidence interval {CI} − 2.68 to − 1.10]; n = 176) and at 8 weeks of follow-up (mean difference − 2.41 [95% CI − 3.36 to − 1.46]; n = 166). One double-blind crossover RCT (n = 32) reported that, compared with amitriptyline, nabilone—a synthetic analogue to tetrahydrocannabinol (THC)—improved Insomnia Severity Index scores after 2 weeks of treatment (adjusted difference − 3.25 [95% CI − 5.26 to − 1.24]) and resulted in a more restful sleep as a sub-measure of the Leeds Sleep Evaluation Questionnaire (LSEQ) (difference 0.48 [95% CI 0.01–0.95]) but with no effect on overall sleep quality as measured by the LSEQ. In a single ascending-dose RCT (n = 9), THC reduced sleep-onset latency compared with placebo at 10 mg, 20 mg and 30 mg doses (mean difference − 43.00 min [95% CI − 82.76 to − 3.24], − 62.00 [95% CI − 103.60 to − 20.40] and − 54.00 [95% CI − 103.93 to − 4.07], respectively). All the included studies were assessed as poor quality, mainly due to small sample sizes, short treatment periods, uncertain clinical significance and high risk of bias.

Conclusions

Few studies have examined the efficacy of cannabinoids in the treatment of insomnia disorder. Despite some possible signals for efficacy, the heterogeneity of participants, interventions, efficacy outcomes and results, and the high risk of bias across included trials, do not reliably inform evidence-based practice. This review highlights shortcomings in the existing literature, including lack of diagnostic clarity, poorly defined participant groups, non-standardised interventions and studies of inappropriate design, duration and power to detect clinically meaningful outcomes. Further research in the form of high-quality RCTs are required before drawing any conclusions about the efficacy of cannabinoids in the treatment of insomnia disorder.

Trial Registration

PROSPERO registration number, CRD42020161043.

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References

  1. American Psychiatric Association. (Institution), American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM–5). 2012.

  2. Sateia MJ. International classification of sleep disorders-third edition highlights and modifications. Chest. 2014;146:1387–94.

    PubMed  Google Scholar 

  3. Macêdo P, Neves G, Poyares DLRD, da Gomes MMM, Macedo P, Neves G, et al. Insomnia current diagnosis: an appraisal. Rev Bras Neurol. 2015;51:62–8.

    Google Scholar 

  4. Krystal AD, Prather AA, Ashbrook LH. The assessment and management of insomnia: an update. World Psychiatry. 2019;18:337–52.

    PubMed  PubMed Central  Google Scholar 

  5. Bollu P, Kaur H. Sleep medicine: insomnia and sleep. Mo Med. 2019;116(1):68–75.

    PubMed  PubMed Central  Google Scholar 

  6. Taylor DJ, Mallory LJ, Lichstein KL, Durrence HH, Riedel BW, Bush AJ. Comorbidity of chronic insomnia with medical problems. Sleep. 2007;30:213–8.

    PubMed  Google Scholar 

  7. Bjorøy I, Jørgensen VA, Pallesen S, Bjorvatn B. The prevalence of insomnia subtypes in relation to demographic characteristics, anxiety, depression, alcohol consumption and use of hypnotics. Front Psychol. 2020;11:527.

    PubMed  PubMed Central  Google Scholar 

  8. Roth T. Insomnia: definition, prevalence, etiology, and consequences. J Clin Sleep Med. 2007;3:3–6.

    Google Scholar 

  9. Léger D, Guilleminault C, Bader G, Lévy E, Paillard M. Medical and socio-professional impact of insomnia. Sleep. 2002;25:621–5.

    Google Scholar 

  10. Daley M, Morin CM, LeBlanc M, Grégoire J-P, Savard J. The economic burden of insomnia: direct and indirect costs for individuals with insomnia syndrome, insomnia symptoms, and good sleepers. Sleep. 2009;32:55–64.

    PubMed  PubMed Central  Google Scholar 

  11. Stoller MK. Economic effects of insomnia. Clin Ther. 1994;16:873–97.

    CAS  PubMed  Google Scholar 

  12. Straten A Van, Zweerde T Van Der, Kleiboer A, Cuijpers P, Morin CM, Lancee J. Cognitive and behavioral therapies in the treatment of insomnia: a meta-analysis. Sleep Med Rev. 2017;1–14.

  13. Riemann D, Baglioni C, Bassetti C, Bjorvatn B, Dolenc Groselj L, Ellis JG, et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017;26:675–700.

    PubMed  Google Scholar 

  14. van der Zweerde T, Bisdounis L, Kyle SD, Lancee J, van Straten A. Cognitive behavioral therapy for insomnia: a meta-analysis of long-term effects in controlled studies. Sleep Med Rev. 2019;48:101208.

    PubMed  Google Scholar 

  15. Cheung J, Ji X, Morin CM. Cognitive behavioral therapies for insomnia and hypnotic medications: considerations and controversies. Sleep Med Clin. 2019;14:253–65.

    PubMed  Google Scholar 

  16. Vaughn LK, Denning G, Stuhr KL, De Wit H, Hill MN, Hillard CJ. Endocannabinoid signalling: has it got rhythm? Br J Pharmacol. 2010;160:530–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Pacher P, Batkai S, Kunos G, Baktal S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy PÁL. Pharmacol Rev. 2006;58:389–462.

    CAS  PubMed  Google Scholar 

  18. Babson KA, Bonn-Miller MO. Sleep disturbances: implications for cannabis use, cannabis use cessation, and cannabis use treatment. Curr Addict Rep. 2014;1:109–14.

    Google Scholar 

  19. Murillo-Rodríguez E. The role of the CB1 receptor in the regulation of sleep. Prog Neuro-Psychopharmacol Biol Psychiatry. 2008;32:1420–7.

    Google Scholar 

  20. Kesner AJ, Lovinger DM. Cannabinoids, endocannabinoids and sleep. Front Mol Neurosci. 2020;13:125.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Nicholson AN, Turner C, Stone BM, Robson PJ. Effect of Δ-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults. J Clin Psychopharmacol. 2004;24:305–13.

    CAS  PubMed  Google Scholar 

  22. Finlay DB, Sircombe KJ, Nimick M, Jones C, Glass M. Terpenoids from cannabis do not mediate an entourage effect by acting at cannabinoid receptors. Front Pharmacol. 2020;11:1–9.

    Google Scholar 

  23. Peever J, Fuller PM. The biology of REM sleep. Curr Biol. 2017;27:R1237–48.

    CAS  PubMed  Google Scholar 

  24. Léger D, Debellemaniere E, Rabat A, Bayon V, Benchenane K, Chennaoui M. Slow-wave sleep: from the cell to the clinic. Sleep Med Rev. 2018;41:113–32.

    PubMed  Google Scholar 

  25. Prospero-Garcia O, Amancio-Belmont O, Becerril-Melendez A, Ruiz-Contreras A, Mendez-Diaz M. Endocannabinoids and sleep. Neurosci Biobehav Rev. 2016;71:671–9.

    CAS  PubMed  Google Scholar 

  26. Garcia AN, Salloum IM. Polysomnographic sleep disturbances in nicotine, caffeine, alcohol, cocaine, opioid, and cannabis use: a focused review. Am J Addict. 2015;24:590–8.

    PubMed  Google Scholar 

  27. Linares IMP, Guimaraes FS, Eckeli A, Crippa ACS, Zuardi AW, Souza JDS, et al. No acute effects of cannabidiol on the sleep-wake cycle of healthy subjects: a randomized, double-blind, placebo-controlled, crossover study. Front Pharmacol. 2018;9:1–8.

    Google Scholar 

  28. Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Braz J Psychiatry. 2008;30:271–80.

    PubMed  Google Scholar 

  29. Pertwee RG, Ross RA, Craib SJ, Thomas A. (−)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. Eur J Pharmacol. 2002;456:99–106.

    CAS  PubMed  Google Scholar 

  30. Carlini E, Cunha J. Hypnotic and antiepileptic effects of cannabidiol. J Clin Pharmacol. 1981;21:417S-427S.

    CAS  PubMed  Google Scholar 

  31. Zuardi AW, Guimaraes FS, Moreira AC. Effect of cannabidiol on plasma prolactin, growth hormone and cortisol in human volunteers. Braz J Med Biol Res Rev Bras Pesqui Med Biol. 1993;26:213–7.

    CAS  Google Scholar 

  32. Bridgeman MBM, Abazia DDT. Medicinal cannabis: history, pharmacology, and implications for the acute care setting. Pharm Ther. 2017;42:180–8.

    Google Scholar 

  33. Walsh Z, Callaway R, Belle-isle L, Capler R, Kay R, Lucas P, et al. Cannabis for therapeutic purposes: patient characteristics, access, and reasons for use. Int J Drug Policy. 2013;24:511–6.

    PubMed  Google Scholar 

  34. Kuhathasan N, Dufort A, Mackillop J, Gottschalk R, Minuzzi L, Frey BN. The use of cannabinoids for sleep: a critical review on clinical trials. Exp Clin Psychopharmacol. 2019;27:383–401.

    PubMed  Google Scholar 

  35. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). 2013.

  36. Buysse C, Reynolds F, Ill DJ, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28:193–5.

    CAS  PubMed  Google Scholar 

  37. Babson KA, Sottile J, Morabito D. Cannabis, cannabinoids, and sleep: a review of the literature. Curr Psychiatry Rep. 2017;19.

  38. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

    PubMed  PubMed Central  Google Scholar 

  39. Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001;2:297–307.

    PubMed  Google Scholar 

  40. Smith S, Trinder J. Detecting insomnia: comparison of four self-report measures of sleep in a young adult population. J Sleep Res. 2001;10:229–35.

    CAS  PubMed  Google Scholar 

  41. Parrott AC, Hindmarch I. The Leeds Sleep Evaluation Questionnaire in psychopharmacological investigations—a review. Psychopharmacology. 1980;71:173–9.

    CAS  PubMed  Google Scholar 

  42. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366.

  43. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:4–10.

    Google Scholar 

  44. Duval S, Tweedie R. A nonparametric “trim and fill” method of accounting for publication bias in meta-analysis. J Am Stat Assoc. 2000;95:89–98.

    Google Scholar 

  45. Cousens K, DiMascio A. Delta-9 THC as an hypnotic—an experimental study of three dose levels. Psychopharmacologia. 1973;33:355–64.

    CAS  PubMed  Google Scholar 

  46. Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in anxiety and sleep: a large case series. Perm J. 2019;23:18–041.

    PubMed  PubMed Central  Google Scholar 

  47. Ware MA, Fitzcharles MA, Joseph L, Shir Y. The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesth Analg. 2010;110:604–10.

    CAS  PubMed  Google Scholar 

  48. Capano A, Weaver R, Burkman E. Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. Postgrad Med. 2020;132:56–61.

    PubMed  Google Scholar 

  49. Roitman P, Mechoulam R, Cooper-Kazaz R, Shalev A. Preliminary, open-label, pilot study of add-on oral Δ9-tetrahydrocannabinol in chronic post-traumatic stress disorder. Clin Drug Investig. 2014;34:587–91.

    CAS  PubMed  Google Scholar 

  50. Eadie J, Van De Water AT, Lonsdale C, Tully MA, Van Mechelen W, Boreham CA, et al. Physiotherapy for sleep disturbance in people with chronic low back pain: Results of a feasibility randomized controlled trial. Arch Phys Med Rehabil. 2013;94:2083–92.

    PubMed  Google Scholar 

  51. Schutte-Rodin SL, Broch L, Buysee D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4:487–504.

    PubMed  PubMed Central  Google Scholar 

  52. Webb CW, Webb SM. Therapeutic benefits of cannabis: a patient survey. Hawaii J Med Public Health. 2014;73.

  53. Lintzeris N, Driels J, Elias N, Arnold JC, McGregor IS, Allsop DJ. Medicinal cannabis in Australia, 2016: the cannabis as medicine survey (CAMS-16). Med J Aust. 2018;209:211–6.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. School of Psychological Medicine, University of Otago, PO Box 7343, Wellington, 6242, New Zealand

    Chiranth Bhagavan & Giles Newton-Howes

  2. Capital and Coast District Health Board, Private Bag 7902, Wellington, 6242, New Zealand

    Chiranth Bhagavan

  3. Medical Research Institute of New Zealand, Private Bag 7902, Wellington, 6242, New Zealand

    Stacey Kung, Marjan Doppen, Mary John, Iva Vakalalabure, Karen Oldfield & Irene Braithwaite

  4. Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand

    Iva Vakalalabure & Karen Oldfield

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  1. Chiranth Bhagavan
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Correspondence to Chiranth Bhagavan.

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Funding

The Medical Research Institute of New Zealand is supported by the Health Research Council of New Zealand (HRC) (Grant nos. 18/1002, 20/057) by way of an independent research organisation grant, and Dr. Karen Oldfield is supported by the HRC through a clinical training fellow grant. No other sources of funding were used to conduct this study or prepare this manuscript.

Conflict of interest

Dr. Irene Braithwaite and Dr. Karen Oldfield have undertaken unrelated consultant work for RuaBio, ZHM, Whakaora Pharma and Helius Therapeutics. Dr. Irene Braithwaite, Dr. Karen Oldfield and Dr. Giles Newtown-Howes are members of the Medical Cannabis Research Collaborative. Dr. Giles Newton-Howes sits on the New Zealand Pharmacology and Therapeutics Advisory Committee and the international advisory board for The Australian Centre for Cannabinoid Clinical and Research Excellence. Chiranth Bhagavan, Stacey Kung, Marjan Doppen, Mary John and Iva Vakalalabure have no conflicts of interest that are directly relevant to the content of this article.

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Author contributions

Protocol development: IV, MJ, GNH, IB. Literature search: IV, MJ. Title and abstract review: all authors. Interpretation of findings: all authors. Draft manuscript: CB, MD, SK. Final revision of manuscript: all authors. Approval for publication: all authors. Supervision: IB, GNH.

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Bhagavan, C., Kung, S., Doppen, M. et al. Cannabinoids in the Treatment of Insomnia Disorder: A Systematic Review and Meta-Analysis. CNS Drugs 34, 1217–1228 (2020). https://doi.org/10.1007/s40263-020-00773-x

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