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.

中文翻译：

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大麻素治疗失眠症：系统评价和荟萃分析

背景

失眠与严重的合并症、残疾和对生活质量的影响有关，尽管药物治疗和心理治疗取得了进展，但它仍然是社会的重大负担。大麻素作为治疗失眠症的药物正在获得认可。

客观的

我们进行了系统评价和荟萃分析，以评估大麻素治疗失眠症的疗效。

方法

我们对 PubMed、Cochrane 图书馆、MEDLINE 和护理和相关健康文献累积索引从成立到 2019 年 12 月 5 日的完整数据库进行了系统评价，并再次在数据提取之前，用于研究基于大麻的产品用于治疗成人失眠症。纳入标准是 (1) 临床研究，(2) 年龄 ≥ 18 岁的参与者，(3) 根据同期诊断标准正式诊断或使用经过验证的仪器量化的失眠症，以及 (4) 将基于大麻的产品与护理标准进行比较，安慰剂或镇静剂。没有施加语言限制。非初级研究、动物研究和大麻引起的失眠研究被排除在外。偏倚风险评估使用随机对照试验 (RCT) 的 RoB 2 工具和非随机研究的偏倚风险 - 非随机试验的干预 (ROBINS-I) 工具。异质性评估我²统计。

结果

共纳入了五项研究（两项 RCT 和三项非随机研究），涉及 219 名研究参与者，其中三项可以合并。三项非随机研究提供了匹兹堡睡眠质量指数问卷评分的数据，显示在 ≤ 4 周的随访中大麻素具有良好的效果（平均差 - 1.89 [95% 置信区间 {CI} - 2.68 至 - 1.10] ；n  = 176) 和 8 周的随访（平均差异 - 2.41 [95% CI - 3.36 至 - 1.46]；n  = 166）。一项双盲交叉 RCT ( n = 32) 报告称，与阿米替林相比，nabilone——一种四氢大麻酚 (THC) 的合成类似物——在治疗 2 周后改善了失眠严重程度指数评分（调整后的差异 - 3.25 [95% CI - 5.26 至 - 1.24]）并导致作为 Leeds Sleep Evaluation Questionnaire (LSEQ) 的子测量，更安静的睡眠（差异 0.48 [95% CI 0.01–0.95]）但对 LSEQ 测量的整体睡眠质量没有影响。在单次递增剂量 RCT ( n = 9)，与安慰剂相比，10 毫克、20 毫克和 30 毫克剂量的 THC 减少了入睡潜伏期（平均差异 - 43.00 分钟 [95% CI - 82.76 至 - 3.24]， - 62.00 [95% CI - 103.60 至 - 20.40] 和 - 54.00 [95% CI - 103.93 到 - 4.07]，分别）。所有纳入的研究均被评估为质量差，主要是由于样本量小、治疗周期短、临床意义不确定和偏倚风险高。

结论

很少有研究检查大麻素治疗失眠症的功效。尽管存在一些可能表明疗效的信号，但参与者、干预措施、疗效结局和结果的异质性以及纳入试验的高偏倚风险并不能可靠地告知循证实践。本综述强调了现有文献中的缺点，包括诊断不明确、参与者群体定义不明确、非标准化干预措施以及设计不当的研究、持续时间和检测临床意义结果的能力。在得出关于大麻素治疗失眠症疗效的任何结论之前，需要以高质量 RCT 的形式进行进一步研究。

试用注册

PROSPERO 注册号，CRD42020161043。