Use of Cannabidiol in the Management of Insomnia: A Systematic Review

Abstract

Background:

Cannabidiol (CBD), one of the major cannabinoids derived from the cannabis plant, is available over the counter. CBD is often used by patients for the management of insomnia, yet research supporting CBDs effectiveness as a treatment for insomnia is inadequate.

Objective:

The objective of this review was to critically evaluate the literature regarding the therapeutic benefits of CBD in the management of insomnia.

Methods:

Results:

Thirty-four studies were eligible for inclusion. All studies reported improvement in the insomnia symptoms of at least a portion of their participants. Of the 34 studies, 19 studies used CBD predominant therapy and 21 studies used nearly equal ratios of CBD to Δ⁹-tetrahydrocannabinol (THC). Of the studies that performed hypothesis testing, 4 of 7 studies with a CBD predominant arm and 12 of 16 studies with a nearly equal ratio of CBD to THC arm reported significant improvement in insomnia outcomes. However, only 2 of the 34 studies focused on patients with insomnia, of which 1 study was a case report. Additionally, several studies used nonvalidated subjective measures, and most studies failed to include objective measures for symptom assessment.

Conclusions:

The results of our systematic review suggest that CBD alone or with equal quantities of THC may be beneficial in alleviating the symptoms of insomnia. Nevertheless, future research assessing CBDs effectiveness in population of patients specifically with insomnia utilizing validated subjective and objective measures is necessary before definitive inferences can be made.

Introduction

Insomnia, a sleep disorder characterized by poor sleep quality and quantity, affects more than 10% of the population.¹ To meet the diagnostic criteria for insomnia, an individual must report difficulty with sleep initiation and maintenance at least three times a week for 3 months or longer.² Insomnia significantly impacts physical and mental health, social functioning, and quality of life and frequently coexists with multiple medical and psychiatric disorders.³ Common medical disorders comorbid with insomnia include chronic pulmonary disorders, hypertension, diabetes, cancer, chronic pain, heart failure, rheumatologic disorders (such as osteoarthritis and rheumatoid arthritis), and neurological disorders (such as Parkinson's and dementia).^4–8 Comorbid psychiatric disorders include depression, anxiety, substance use disorders, and post-traumatic stress disorder (PTSD).^9–12 In addition, insomnia is also frequently comorbid with other sleep disorders such as sleep apnea, limb movement disorders of sleep, and circadian sleep disorders.¹³

Despite the pervasive negative effects of insomnia on health and quality of life, currently available management modalities for insomnia have several limitations. Cognitive behavioral therapy (CBT) is the recommended first-line management for insomnia.¹⁴ Although CBT has clinically meaningful effect sizes, compliance to CBT remains a challenge.¹⁵ Reasons for this include the patient's time commitment to engage in the CBT strategies and changes in behaviors to improve sleep (sleep hygiene), which is challenging for individuals who are already chronically sleep deprived. For patients who have suboptimal clinical responses with CBT, a limited number of medications have been approved for the management of insomnia and include eszopiclone, zaleplon, zolpidem, lemborexant, suvorexant, ramelteon, and low-dose doxepin.¹⁶

While these medications can at least partially alleviate insomnia symptoms, they all share the risk for common side effects such as central nervous system depression (impaired alertness and motor coordination), abnormal thinking and behavior changes, complex sleep-related behaviors, and a risk of worsening depression. These side effects along with concerns regarding dependence to these medications impact patient willingness to consider pharmacotherapy.¹⁵ Therefore, despite limited evidence of efficacy and safety, patients frequently resort to over-the-counter medications such as diphenhydramine, dietary supplements such as melatonin, and botanicals such as valerian, chamomile, kava, passion flower, hops, and cannabis.^17,18

In the United States, the 2018 farm bill legalized the production of hemp and hemp-derived products as agricultural products, removing them from their prior designation of controlled substances.¹⁹ This made cannabidiol (CBD) legally available over the counter across the United States. CBD is one of the cannabinoids derived from the cannabis plant, and it is one of two major cannabinoids in therapeutic use today, the other being Δ⁹-tetrahydrocannabinol (THC).²⁰ CBD differs from THC in its lack of psychoactive effects, making it less controversial for therapeutic use than THC. The increased availability of CBD over the counter has resulted in heightened marketing of CBD for a wide variety of symptoms, including pain, anxiety, cancer treatment side effects, and insomnia. The majority of these indications are, however, not supported by rigorous clinical studies.

Observational studies report that sleep difficulties are one of the primary reasons for cannabis/CBD use.^21,22 However, research on CBDs effectiveness as a treatment for insomnia is scant and varying in results.²³ The majority of studies evaluating cannabinoids and sleep have focused on the effects of THC; very few studies have specifically examined CBD.^24–26 For example, a recent systematic review by Kuhathasan et al²⁷ examining cannabinoids and sleep reported 13 studies on nabiximols (1:1 ratio of CBD to THC), but only 1 study that examined the effectiveness of CBD alone. Another systematic review on cannabinoids and sleep that included at least three studies with CBD reported improvements in several sleep outcomes but concluded that there was insufficient evidence for their use in clinical practice.²⁵ Although it appears that cannabinoids may be beneficial in the management of insomnia and sleep disorders, more research is needed to determine if CBD specifically is beneficial in the management of insomnia.

The aim of this systematic review was to evaluate the possible benefits of CBD in the management of insomnia. While past reviews on this topic have focused broadly on cannabinoids in the treatment of sleep disorders, this review specifically examines the effects of CBD on insomnia.

Methods

The protocol for this review was registered with the PROSPERO International Prospective Register of Systematic Reviews (ID: CRD42021257197). This review followed the 2020 Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines.²⁸

Search strategies

A comprehensive search of the following databases from inception to December 29, 2021, was conducted: Ovid MEDLINE^® and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. One reviewer also searched the reference lists of previous reviews for relevant publications. The specific inclusion criteria were as follows: (1) human participants, (2) age 18 years or older, (3) written in English, (4) measured CBD use, and (5) at least some participants took CBD in an equal or higher concentration compared with other cannabinoids taken simultaneously by the individual. Studies of any design were eligible for inclusion. Review articles, conference proceedings, book chapters, and study protocols were excluded. The complete search strategy for each database can be found in Table 1.

Table 1.

Search Strategies for All Databases

No.	Searches for the following databases: Embase 1988+, Ovid MEDLINE^® and Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations 1996+, APA PsycInfo 1987+, EBM Reviews—Cochrane Central Register of Controlled Trials 1991+, EBM Reviews—Cochrane Database of Systematic Reviews 2005+
1	exp “Sleep Initiation and Maintenance Disorders”/
2	^*insomnia/
3	insomnia.ti,ab.
4	(sleep adj3 (initiat^* or maintenance or maintain^) adj3 (disorder^ or dysfunction)).ti,ab,hw,kw.
5	(“subwakefullness syndrome^” or dyssomnia^ or “sleep initiation dysfunction” or “early awakening” or sleeplessness or “sleep-wake transition disorder”).ti,ab.
6	(sleep^* adj1 (disturb^* or disrupt^* or restrict^* or duration or fragment^* or hygiene or interrupt^* or efficien^* or continuity)).ti,ab,hw,kw.
7	or/1-6
8	(cannabidiol or epidyolex or nabidiolex or sativex).ti,ab,hw,kw. or (“gwp 42003p” or “gwp-42003-p” or gwp42003p).ti,ab.
9	exp cannabidiol/
10	or/8-9
11	7 and 10
12	(conference abstract or conference review or editorial or erratum or note or addresses or autobiography or bibliography or biography or blogs or comment or dictionary or directory or interactive tutorial or interview or lectures or legal cases or legislation or news or newspaper article or patient education handout or periodical index or portraits or published erratum or video-audio media or webcasts).mp. or conference abstract.st.
13	11 not 12
14	(children or child or youth or young or adolescent^* or adolescence or pediatri^*).ti.
15	13 not 14
16	15 not ((exp animals/or exp nonhuman/) not exp humans/)
17	limit 16 to English language
18	limit 16 to no language specified
19	17 or 18
20	remove duplicates from 19

	Searches for the following database: SCOPUS
1	(TITLE-ABS-KEY (sleep W/3 (initiat^* OR maintenance OR maintain^) W/3 (disorder^ OR dysfunction))) OR (TITLE-ABS-KEY (sleep^* W/1 (disturb^* OR disrupt^* OR restrict^* OR duration OR fragment^* OR hygiene OR interrupt^* OR efficien^* OR continuity))) OR (TITLE-ABS-KEY (“subwakefullness syndrome^” OR dyssomnia^ OR “sleep initiation dysfunction” OR “early awakening” OR sleeplessness OR “sleep-wake transition disorder”))
2	TITLE-ABS-KEY (cannabidiol OR epidyolex OR nabidiolex OR sativex OR “gwp 42003p” OR “gwp-42003-p” OR gwp42003p)
3	1 and 2
4	INDEX(embase) OR INDEX(medline) OR PMID(0^* OR 1^* OR 2^* OR 3^* OR 4^* OR 5^* OR 6^* OR 7^* OR 8^* OR 9^*)
5	3 not 4
6	DOCTYPE(ed) OR DOCTYPE(bk) OR DOCTYPE(er) OR DOCTYPE(no) OR DOCTYPE(sh) OR DOCTYPE(ch)
7	5 not 6
8	LANGUAGE(english)
9	7 and 8

Article screening and data extraction

Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia) was utilized for the article screening process. Two reviewers independently screened each article against the eligibility criteria by abstract and title. Articles that met the eligibility criteria were then moved to the full-text screening stage and screened by two reviewers independently. Two reviewers then independently extracted data from all eligible articles. Disagreements at each step of the screening and data extraction process were settled via discussion with a third reviewer.

During data extraction, only measures pertaining to insomnia (subjective or objective difficulty in falling asleep, staying asleep, or early awakening; restful or refreshing sleep; sleep quality; sleep duration) or placebo were included. For these measures, data for each time point (means and standard deviations or medians and ranges) and intervention details were extracted. Specific data extracted included country in which the study was conducted, sample size, participant demographic information (sex, age, race, ethnicity, body mass index, comorbidities, experience with cannabis), primary and secondary outcomes, intervention characteristics (types of cannabinoids studied, dose route of administration, frequency, and type of cannabinoid strain or product), and funding sources.

Risk of bias assessment

Two reviewers independently assessed the risk of bias utilizing the Agency for Healthcare Research and Quality design-specific criteria.²⁹ The questions used to assess the risk of bias are included in Table 2. Disagreements were settled via discussion with a third reviewer.

Table 2.

Agency for Healthcare Research and Quality Design-Specific Recommended Criteria Questions and Types of Biases

Type of bias, question number	AHRQ questions
Selection bias
Q1	Was treatment adequately randomized (e.g., random number table, computer-generated randomization)?
Q2	Was the allocation of treatment adequately concealed (e.g., pharmacy-controlled randomization or use of sequentially numbered sealed envelopes)?
Q3	Any attempt to balance the allocation between the groups?
Q4	Did the study apply inclusion/exclusion criteria uniformly to all comparison groups?
Q5	Is the selection of the comparison group appropriate?
Q6	Did the strategy for recruiting participants into the study differ across study groups?
Q7	Are baseline characteristics similar between groups? If not, did the analysis control for differences?
Q8	Does the design or analysis control account for important confounding and modifying variables?
Performance bias
Q9	Did researchers rule out any impact from a concurrent intervention or an unintended exposure that might bias results?
Q10	Did variation from the study protocol compromise the conclusions of the study?
Attrition bias
Q11	In cohort studies, is the length of follow-up different between the groups, or in case–control studies, is the time period between the intervention/exposure and outcome the same for cases and controls?
Q12	Was there a high rate of differential or overall attrition?
Q13	Did attrition result in a difference in group characteristics between baseline (or randomization) and follow-up?
Q14	Is the analysis conducted on an intention-to-treat basis?
Detection bias
Q15	Were the outcome assessors blinded to the intervention or exposure status of participants?
Q16	Are the inclusion/exclusion criteria measured using valid and reliable measures, implemented consistently across all study participants?
Q17	Are interventions/exposures assessed using valid and reliable measures, implemented consistently across all study participants?
Q18	Are primary outcomes assessed using valid and reliable measures, implemented consistently across all study participants?
Q19	Are confounding variables assessed using valid and reliable measures, implemented consistently across all study participants?
Reporting bias
Q20	Are the potential outcomes prespecified by the researchers? Are all prespecified outcomes reported?

AHRQ, Agency for Healthcare Research and Quality; Q, question.

Data synthesis

Data were synthesized via summary tables. Study author, year, sample demographic information, intervention/study description, and results of CBD-dominant/equal CBD:THC preparations on insomnia symptoms are reported. The results of all cannabinoid preparations compared with placebo or baseline for clinical trials are also summarized, along with the risk of bias results.

Results

Study identification, screening, and inclusion

Details of the identification, screening, and inclusion of studies are reported in Figure 1. Our primary search identified a total of 286 studies. After duplicates were removed, 209 studies remained for screening. Of the 209 studies, 47 were eligible for full-text review. Following the full-text review, 15 studies were eligible for inclusion. An additional 19 eligible studies were identified through citation searching, resulting in 34 studies^22,30–62 eligible for inclusion in this systematic review.

FIG. 1.

PRISMA flow diagram of identified, included, and excluded articles. PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analyses.

Characteristics of included studies

Details of the included studies can be found in Table 3, and results of clinical trials are included in Table 4. Of the 34 studies included in this systematic review, 18 studies were clinical trials (randomized controlled trials [n=16]^{31,32,39,43,46,47,50–53,55–58,60,61} and nonrandomized experimental studies [n=2]^34,42), 7 were cross-sectional studies,^{22,33,35,37,44,48,49} 5 were cohort studies,^{36,38,41,45,62} 3 were case series,^40,54,59 and 1 was a case report³⁰ (Table 3). Only two studies^30,45 (including one case report) focused specifically on patients with insomnia.

Table 3.

Details of the Included Studies Examining the Use of Cannabidiol for the Management of Insomnia Symptoms

First author (year)	Study design and sample characteristics (age [years]^*; sex, M, F, n (%); population description)	Intervention (cannabinoid type, dose, and timing)	Insomnia measure (insomnia outcome, measure utilized)	Findings related to CBD and insomnia
Berger (2020)³⁰	Case report Age: 20 Sex: 1 (100) M Patients with longstanding and severe social anxiety, depression, chronic insomnia, and subthreshold psychotic experiences	CBD administered for 6 months, escalated from 200 to 800 mg/day over an 8-week period	Chronic insomnia/sleep disturbances—self-report	Self-reported improvement in sleep
Berman (2004)³¹	Randomized crossover trial Age: 39 (range 23–63) Sex: 46 (95.8) M, 2 (4.2) F Patients with brachial plexus injury treated at the Royal National Orthopedic Hospital	Three groups: 2.5 mg CBD +2.7 mg THC, 2.7 THC, placebo Oromucosal spray; maximum dose of 8 sprays per 3 h interval and a maximum of 48 sprays per 24 h; baseline period of 2 weeks, followed by three 2-week treatment periods during each of which patients received one of three oromucosal spray preparations	Sleep quality—NRS Sleep disturbance—number of times woken due to pain	Sleep quality in the THC group improved significantly from a mean score of 4.8 at baseline to 6.0 compared with placebo (95% CI: 0.33 to 1.24; p<0.001), and sleep disturbances improved significantly from a mean score of 1.3 at baseline to 1 compared with placebo (95% CI: −0.49 to −0.16; p<0.001). Sleep quality in the CBD:THC group improved significantly from a mean score of 4.8 at baseline to 5.9 compared with placebo (95% CI: 0.09 to 1.01; p=0.019), and sleep disturbances improved significantly from a mean score of 1.3 at baseline to 1.1 compared with placebo (95% CI −0.37 to −0.04; p=0.017).
Blake (2006)³²	Randomized controlled trial Age: 62.8 (9.8) Sex: 12 (21) M, 46 (79) F Patients with rheumatoid arthritis	Two groups: 2.5 mg CBD +2.7 mg THC, placebo Oromucosal spray; Starting dose was one actuation, increased by one actuation every 2 days to a maximum of six actuations, stable dosing was then maintained for a further 3 weeks; 5-week treatment duration	Sleep quality—single-item NRS	Sleep quality improved significantly from baseline with a difference of −1.17 relative to placebo (95% CI: −2.20 to −0.14; p=0.027).
Boehnke (2021)³³	Cross sectional Age: 56.6 (12) Sex: 135 (4.3) M, 2566 (95) F Patients with fibromyalgia	Varying/unknown routes of CBD administration, dosages, duration, and frequency of use	Insomnia/sleep problems—7-point Likert scale	40.1% of participants with insomnia/sleep problems reported “much” or “very much” improvement following CBD use.
Brady (2004)³⁴	Nonrandomized experimental Age: 48 (range 31–64) Sex: 4 (19) M, 17 (81) F Patients with advanced MS and troublesome lower urinary tract symptoms refractory to maximal conventional treatment	Two groups: 2.5 mg THC +2.5 mg CBD, 2.5 mg THC Oral spray; THC+CBD or THC once per day the first 2 weeks of treatment, then a maximum permitted daily dose was 120 mg each for CBD+THC or 120 mg THC (48 sprays)	Difficulty sleeping—VAS (0–100)	No significant differences (p<0.05) were found for sleep difficulties between baseline (mean=49.78, SD=26.05) and follow-up (mean=32.00, SD=25.95) in the THC:CBD group.
Braley (2020)³⁵	Cross sectional Age: 51.2 (12.3) Sex: 239 (19.6) M, 978 (80.4) F Patients with MS	Preferred THC:CBD ratio: low THC+low CBD, high THC+high CBD, CBD monotherapy or predominant therapy, THC monotherapy or predominant therapy Varying/unknown routes of administration, dosages, and frequency of use	Ability to fall asleep—NRS (0–10) Ability to stay asleep—NRS (0–10) More restful/refreshing sleep—NRS (0–10) Relieves pain that interferes with sleep—NRS (0–10) Sleep disturbance—PROMIS Sleep Disturbance—8b (normed T scores [range 0–100, mean=50, SD=10])	In the low THC+low CBD group, 43% reported improved ability to fall asleep, 14% improved ability to stay asleep, 29% more restful/refreshing sleep, 29% relieves pain that interferes with sleep. In the high THC+high CBD group, 75% reported improved ability to stay asleep, 53% improved ability to stay asleep, 33% more restful/refreshing sleep, 69% relieves pain that interferes with sleep. In the CBD monotherapy or predominant therapy group, 42% reported improved ability to stay asleep, 36% improved ability to stay asleep, 22% more restful/refreshing sleep, 38% relieves pain that interferes with sleep.
Capano (2020)³⁶	Cohort Age: 56.1 (range 39–70) Sex: 31 (32) M, 66 (68) F Patients with chronic pain who have been on opioids for at least 1 year	Oral soft gels; ∼30 mg CBD-rich extract daily for 8 weeks	Sleep quality—PSQI (0–21)	Sleep quality significantly improved from 12.09 at baseline (95% CI 11.37 to 12.80) to 10.7 at 4 weeks (95% CI 9.99 to 11.44) to 10.3 at 8 weeks (95% CI 9.48 to 11.20; p=0.03).
Carrubba (2021)³⁷	Cross sectional Age: 44.1 (13.9) Sex: 96 (100) F Patients with diagnosis of pelvic and perineal pain, dyspareunia, or endometriosis	Three groups: CBD-dominant, THC-dominant, THC+CBD Varying/unknown routes of administration, dosages, and frequency of use	Sleeplessness and insomnia—self-reported	50% (n=3) of participants taking CBD reported improvement in sleep. 100% (n=3) of participants taking THC reported improvement. 73.3% (n=11) of participants taking THC+CBD reported improvement.
Casarett (2019)³⁸	Cohort Age: (of those with insomnia) 34 (range 18–76) Sex: (of those with insomnia) 375 (43.2%) M, 494 (56.8%) F Patients who self-reported cannabis use for a variety of symptoms	Continuum: high and low CBD concentration compared with THC Vaporizer; varied/unknown dosage and duration of use	Insomnia—self-ratings of efficacy of cannabis, defined as a 3-point reduction in insomnia (0–10 NRS)	For participants taking 100% CBD, slightly less than 45% reported a 3-point improvement in their insomnia. More participants taking roughly equal CBD:THC concentrations reported a 3-point improvement in their insomnia than participants taking 100% CBD.
Collin (2010)³⁹	Randomized controlled trial Age: 47.5 (9.61) Sex: 130 (39) M, 207 (61) F Patients with MS with spasticity and not relieved with current therapy	Two groups: 2.5 mg CBD +2.7 mg THC, placebo Oromucosal spray; maximum dose of 8 sprays per 3 h interval and a maximum of 48 sprays per 24 h; 14-week treatment duration	Sleep quality—NRS (0–10)	Sleep quality did not improve significantly from baseline compared with placebo (mean=−0.07; p=0.764).
Elms (2019)⁴⁰	Case series Age: 39.9 (17.4) Sex: 3 (27.3) M, 8 (72.7) F Patients with PTSD	Liquid, capsular, or both; mean total starting dose of CBD per day was 33.18 mg (SD=23.34). Mean total dose of CBD at the 8-week follow-up appointment at the conclusion of the study period was 48.64 mg (range: 2–100)	Sleep quality—PCL-5 (asks about “trouble falling or staying asleep”)	38% (n=8) of participants reported subjective improvement in the quality of their sleep.
Gulbransen (2020)⁴¹	Cohort Age: 51.48 (19.1) Sex: 183 (46.1) M, 214 (53.9) F Patients seen in Cannabis Care, a primary care clinic (either referred by their primary care provider or self-referred to the service) prescribed CBD	Oral dropper; 40–300 mg/day of CBD (clinician-recommended dosing to at least 100 mg/day)	“Improved sleep”—assessed as part of positive side effect profile of study	12.3% (n=31) of participants reported improved sleep as a side effect.
Gustavsen (2021)⁴²	Nonrandomized experimental Age: 50 (range 27–74) Sex: 7 (25) M, 21 (75) F Patients with MS and refractory neuropathic pain and/or spasticity	Four groups: THC-dominant, CBD-dominant, high THC+low CBD, equal THC:CBD Sublingual drops; measured at baseline and 4-week follow-up	Sleep disturbances—NRS (1–11)	Sleep disturbances significantly decreased in patients taking THC-containing preparations from a median score of 7.0 (range: 0.0–9.0) to 3.0 (range: 0.0–10; p<0.01), and sleep disturbances also decreased in patients taking CBD-dominant products from a median score of 8.0 (range: 3.0–10) to 0.0 (range 0.0–1.0; p=0.07).
Johnson (2010)⁴³	Randomized controlled trial Age: 60.2 (12.3) Sex: 95 (54) M, 85 (46) F Patients previously using strong opioids for at least 1 week to relieve pain associated with advanced cancer	Three groups: 2.7 mg THC +2.5 mg CBD, 2.7 mg THC, placebo Oromucosal spray; maximum permitted dose was 8 actuations in any 3-h period and 48 actuations in any 24-h period; 2 weeks	Sleep quality—NRS (0–10) Insomnia—EORCT QLQ-C30	No significant group differences were found for sleep quality (mean difference=−0.31, p=0.346) or insomnia (mean difference=−1.05, p=0.833) between the THC:CBD and placebo group (placebo statistics not reported).
Kasper (2020)⁴⁴	Cross sectional Age: 25 (5) Sex: 517 (100) M Professional United Kingdom rugby players	Oils or capsules; varying/unknown dosages and concentrations of CBD	Purpose-developed survey—“for what reasons do/did you use CBD—improve sleep quality”	78% of respondents who reported using CBD cited sleep difficulties as their reason for CBD use. Of those who reported sleep difficulties as their reason for taking CBD, 41% endorsed “improved sleep” as a perceived benefit.
Kuhathasan (2021)⁴⁵	Cohort study Age: 36.32 (11.65) Sex: 42.6% (422/991) self-identified M, 56.1% (556/991) self-identified F Canadian medicinal cannabis users with insomnia who used the medicinal cannabis tracking app “Strainprint” to monitor changes in insomnia symptoms	Varying/unknown routes of cannabinoid (CBD, balanced hybrid, indica, indica hybrid, sativa, sativa hybrid) strains administration, dosages, duration, and frequency of use	Insomnia symptom severity rating—self-reported	Insomnia symptoms improved significantly (p<0.001) from baseline for cannabinoid strains of CBD with a change score of 3.074027 (0.114947), balanced hybrid with a change score of 3.461359 (0.112701), indica with a change score of 3.661426 (0.094507), indica hybrid with a change score of 3.589259 (0.097939), sativa with a change score of 2.916945 (0.163117), and sativa hybrid with a change score of 3.470149 (0.171074).
Langford (2013)⁴⁶	Randomized controlled trial Age: A: 48.97 (10.47), B: 48.01 (10.12) Sex: A: 109 (32) M, B:17 (40) M; A: 230 (68) F, B: 230 (68) F Patients with MS and chronic neuropathic pain	Two (and two phases): 2.5 mg CBD +2.7 mg THC, placebo Oromucosal spray; Patients were restricted to a maximum of 12 sprays per 24-h period (Phase B escalated dose to 12 daily sprays); A: 14 weeks, B: 18 weeks	Sleep quality—NRS (0–10)	Sleep quality did not improve significantly from baseline in phase A with a difference of −1.96 relative to placebo (p=0.833). Sleep quality improved significantly from baseline in phase B with a difference of −0.07 relative to placebo (p=0.015)
Linares (2018)⁴⁷	Randomized crossover trial Age: 29.3 (8.5) Sex: 12 (46) M, 14 (54) F Healthy volunteers with no sleep problems	Two groups: 300 mg CBD, placebo Oral gelatin; CBD or placebo was administered 30 min before the polysomnographic recordings began	Sleep onset latency—polysomnography (minutes) Sleep efficiency—polysomnography (%) Total sleep time—polysomnography (minutes)	No significant differences (p>0.05) were found between the administration of CBD compared with placebo for sleep onset latency (mean=9.8, SD=8.4; mean=13.4, SD=12.8), sleep efficiency (mean=87.1, SD=10.2; mean=85.3, SD=13.2), or total sleep time (mean=388.1, SD=51.4; mean=389.3, SD=66.2).
Lovecchio (2021)⁴⁸	Cross sectional Age: 58.0 (14.5) Sex: 123 (58%) M, 91 (42%) F Patients presenting for evaluation by one of nine spine surgeons at a single center in New York, New York, during October 2019	Varying/unknown routes of CBD administration, dosages, duration, and frequency of use	Use of CBD for insomnia (yes/no) and if improved sleep was a benefit experienced from CBD (yes/no)—self-reported	25.9% (n=14) of participants used CBD for insomnia and 33.3% (n=18) of participants reported improved sleep as a benefit experienced from CBD.
Mathur (2020)⁴⁹	Cross sectional Age: median 49 (range 38–59) Sex: 32 (8.6) M, 339 (91.4) F Adults with AIH	Sublingual drops, oral capsule, inhalation, topically; varying/unknown dosages, duration, and frequency of CBD use	Purpose-developed survey—questions about reasons for CBD use and if symptoms improved with CBD use	93% (54/59) of participants who endorsed CBD use reported improvement in sleep.
Moltke (2021)²²	Cross sectional Age: 3.9%, 18–24; 23.9%, 25–34; 24.9%, 35–44; 23.4%, 45–54; 14.3%, 55–64; 9.4%, 65+ Sex: 150 (38.8) M, 237 (61.2) F Current/past CBD users identified via email databases of CBD brands/retailers and social media	Varying/unknown routes of CBD administration, dosages, duration, and frequency of use	Time to fall asleep—Self-reported	48.2% (73/124) reported CBD helped them fall asleep faster (23.4% reported CBD did not make a difference and they still had a hard time falling asleep).
Nicholson (2004)⁵⁰	Randomized crossover trial Age: M 28.8 (range 24–34), F 21.8 (21–22) Sex: 4 (50) M, 4 (50) F Healthy young adults without significant medical or psychiatric conditions	Four groups: 15 mg THC, 5 mg THC +5 mg CBD, 15 mg THC +15 mg CBD, placebo Oromucosal spray; doses given via six actuations over the course of 30 min beginning at 10 pm	Sleep onset latency—polysomnography (minutes) Sleep efficiency index—polysomnography (log) Total sleep time—polysomnography (minutes) Number of awakenings	No significant differences (p>0.05) were found between the administration of 5 mg THC +5 mg CBD (mean=22.56) or 15 mg THC +15 mg CBD (mean=23.5) compared with placebo (mean=24.63) for sleep onset latency. No significant differences (p>0.05) were found between the administration of 5 mg THC +5 mg CBD (mean=0.92) or 15 mg THC +15 mg CBD (mean=0.84) compared with placebo (mean=0.89) for sleep efficiency. No significant differences (p>0.05) were found between the administration of 5 mg THC +5 mg CBD (mean=443.83) or 15 mg THC +15 mg CBD (mean=404.56) compared with placebo (mean=429.13) for total sleep time. No significant differences (p>0.05) were found between the administration of 5 mg THC +5 mg CBD (mean=12.5) or 15 mg THC +15 mg CBD (mean=14.25) compared with placebo (mean=13.63) for number of awakenings.
Notcutt (2004)⁵¹	Randomized crossover trial (34 N of 1) Age: 46.7 (10.1) Sex: 11 (32.4) M, 23 (67.6) F Patients with chronic stable pain, poorly responsive to other modalities of control	Four groups: 2.5 mg CBD, 2.5 mg of THC, 2.5 mg THC +2.5 mg CBD, placebo Sublingual spray; individually titrated, in each group for two separate 1-week periods	Duration of sleep (hours)—self-reported Quality of sleep—self-reported (Good, Fair, Poor)	Participants reported significantly better sleep quality when taking 2.5 mg CBD (IQR=36.9, range=47.9–28.6), 2.5 mg of THC (IQR=42.9, range=57.2–35.7), or 2.5 mg THC +2.5 mg CBD (IQR=55.4, range=78–34.5) compared with placebo (IQR=17, range=35.7–3.6); p<0.05). There were no mean differences between the CBD (mean=6.4, SD=1.4), THC (mean=6.7, SD=1.3), or THC+CBD (mean=6.8, SD=1.3), and placebo (mean=6.3, SD=1.6) in their effect on sleep duration.
Novotna (2011)⁵²	Randomized controlled trial Age: 48.6 (9.33) Sex: 96 (40) M, 145 (60) F Patients with MS spasticity not fully relieved with current antispasticity therapy	(Phase B) Two groups: 2.5 mg CBD +2.7 mg THC, placebo Oromucosal spray; maximum of 12 sprays in any 24-h period, 12-week study duration	Sleep disturbance—NRS	Participant scores in the CBD+THC group differed by a mean of −0.13 from baseline compared with placebo scores, which differed by a mean of 0.75. The group mean scores were significantly different with a mean difference between groups of −0.88 (p<0.0001).
Nurmikko (2007)⁵³	Randomized controlled trial Age: Sativex: 52.4 (15.8), placebo: 54.3 (15.2) Sex: 51 (40.8) M, 74 (59.2) F Patients with unilateral peripheral neuropathic pain and allodynia	Two groups: 2.5 mg CBD +2.7 mg THC, placebo Oromucosal spray; maximum dose of 8 sprays per 3-h interval and a maximum of 48 sprays per 24 h; 5-week treatment duration	Sleep disturbance—single item rating the number of times they woke in the previous night due to symptoms	Sleep disturbances improved significantly from baseline with a mean difference of −0.43 relative to placebo (95% CI −0.67 to −0.19; p=0.001).
Pacheco (2021)⁵⁴	Case series Age: 32.5 (6.9) Sex: 6 (46.1) M, 7 (53.8) F Non-frontline hospital employees (individuals in administration, teaching, research) during the COVID-19 pandemic	Oral dose; 165 mg CBD twice a day; 3-week treatment duration	Insomnia—7-item Insomnia Severity Index	CBD was associated with significant improvements in insomnia (p<0.05).
Portenoy (2012)⁵⁵	Randomized controlled trial Age: 58 (12.2) Sex: 186 (51.7) M, 174 (48.3) F Opioid-treated cancer patients with poorly controlled chronic pain	Four groups: (all 2.5 mg CBD +2.7 mg THC per spray) 1–4 sprays per day, 6–10 sprays per day, 11–16 sprays per day, placebo Oromucosal spray; 35-day study duration	Sleep disturbance—NRS (0–10)	Participant scores in the low-dose group differed by a mean of −0.88 from baseline, the medium-dose group differed by −0.33, and the high-dose group differed by −0.08. The mean change scores were significantly different from placebo for only the low-dose group (p=0.003).
Rog (2005)⁵⁶	Randomized controlled trial Age: 49.2 (8.3) Sex: 14 (21.2) M, 52 (78.8) F Patients with central neuropathic pain syndromes due to MS	Two groups: 2.5 mg CBD +2.7 mg THC, placebo Oromucosal spray; Patients were advised to increase the number of sprays stepwise on consecutive days up to 48 sprays in 24 h, patients were advised to take no more than 8 sprays within any 3 h interval and refrain from up-titrating the daily dose by more than 50% from the previous day; 4-week treatment duration	Sleep disturbance due to pain—NRS-11	Sleep disturbances improved significantly from baseline with a difference of −1.39 relative to placebo (95% CI −2.27 to −0.50; p=0.003).
Schloss (2021)⁵⁷	Randomized controlled trial Age: 53.3 (12.6) Sex: 42 (50.6) M, 41 (49.4) F Patients with high-grade gliomas	Two groups: 4.8 mg CBD +4.6 mg THC, 3.8 CBD +15 mg THC Single dose at night before bed that was titrated up to tolerance starting at 0.20 mL (maximum 5 mL in one dose); 12-week treatment duration	Sleep quality—Functional Assessment of Cancer Therapy for Brain Cancer	Sleep improved in both groups (statistical significance for each group separately is unknown).
Serpell (2014)⁵⁸	Randomized controlled trial Age: 57.3 (14.2) Sex: 96 (39) M, 150 (61) F Patients with peripheral neuropathic pain and associated allodynia	Two groups: 2.5 mg CBD +2.7 mg THC, placebo Oromucosal spray; maximum of 8 sprays in a 3-h period up to a maximum of 24 sprays per 24-h period; 14-week treatment duration	Sleep quality—NRS (0–10)	Sleep quality improved significantly from baseline with a mean difference of 0.83 relative to placebo (mean=0.306; p=0.007).
Shannon (2019)⁵⁹	Case series Age: anxiety: 34 (range: 18–70), sleep: 36.5 (range: 18–72) Sex: M with anxiety: 28 (59.6), with sleep disorders: 9 (36.0); F with anxiety: 19 (40.4), with sleep disorders: 16 (64.0) Consecutive adult patients treated with CBD at an outpatient psychiatry practice	Most oral capsule; patients received 25 CBD mg/day; measured at baseline and monthly for 3 months	Sleep quality—PSQI (0–21)	On average, sleep improved for most patients, and these improvements were sustained over time. For patients with anxiety, sleep quality scores changed from a mean of 10.98 (3.43) at baseline to 9.25 (2.46) at the 3-month follow-up. For patients with sleep disorders, scores changed from 13.08 (3.03) at baseline to 9.33 (4.63) at the 3-month follow-up.
Wade (2003)⁶⁰	Randomized crossover trial Age: 48 Sex: 10 (50) M, 10 (50) F Patients with a neurological diagnosis and troublesome symptoms (neuropathic pain, spasticity, muscle spasms, impaired bladder control, and tremor), which were stable and unresponsive to standard treatments	Four groups: 2.5 mg CBD, 2.5 mg THC, 2.5 mg THC +2.5 mg CBD, placebo Sublingual spray; max dose of 120 mg/24 h, 2 weeks per preparation	Sleep quality—VAS (1–10)	Participants reported significantly better sleep quality when taking 2.5 mg THC +2.5 mg CBD (mean=65.3, SD=22.6) compared with placebo (mean=59, SD=24.4; p<0.05), but no differences between the placebo and 2.5 mg CBD (mean=57.9, SD=25.2) or 2.5 mg THC (mean=61.7, SD=25.4; p>0.05).
Wade (2004)⁶¹	Randomized controlled trial Age: Active group: 51.0 (9.4); 27–74 Placebo: 50.4 (9.3); 27–74 Sex: 61 (38.1) M, 99 (61.9) F Patients with MS	Two groups: 2.5 mg CBD +2.7 mg THC, placebo Oromucosal spray; maximum of 120 mg THC and 120 mg CBD per day with no more than 20 mg of each in any 3-h period; 6-week treatment duration	Sleep quality—VAS Sleep duration	Sleep quality improved significantly from baseline with a difference of −7.1 compared with placebo (p=0.047). Sleep disturbances did not improve significantly from baseline with a difference of −9.4 compared with placebo (p=0.198).
Wan (2017)⁶²	Cohort Age: 44.9 (range 1–80) Sex: M 575 (68.8), F 259 (30.9) Online survey of patients using medical cannabis from one Canadian licensed provider	Of 15 cannabis strains reported, the 2 that included CBD were Midnight (11–14% CBD +8–11% THC) and Avidekel (15–18% CBD +15–18% THC) Varying/unknown routes of administration and dosage, 4-month study duration	Sleep disorder—self-reported severity Sleep problems—self-reported severity Sleep—self-reported severity	Of the cannabis strains, Midnight was ranked third for improving sleep disorders. Midnight was ranked second and Avidekel was ranked third for improving sleep problems. Midnight was ranked first and Avidekel was ranked third for improving sleep.

Mean (SD) unless otherwise noted.

AIH, autoimmune hepatitis; CBD, cannabidiol; CI, confidence interval; EORCT QLQ-C30, European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire; F, female; IQR, interquartile range; M, male; MS, multiple sclerosis; NRS, numerical rating scale; PCL-5, Post-traumatic Stress Disorder Checklist; PROMIS, Patient-Reported Outcomes Measurement Information System; PSQI, Pittsburgh Sleep Quality Index; PTSD, post-traumatic stress disorder; SD, standard deviation; THC, Δ⁹-tetrahydrocannabinol; VAS, visual analog scale.

Table 4.

Insomnia Outcome Results of All Cannabinoid Preparations in Clinical Trials

— Signifies no preparation in that category identified; vertical lines signify significant benefits in at least one insomnia outcome compared with placebo (or baseline if no placebo was included); diagonal lines signify benefits (although insignificant) in at least one insomnia outcome compared with placebo (or baseline if no placebo was included); solid fill signifies no benefits in any insomnia outcome compared with placebo (or baseline if no placebo was included).

All THC-containing products were analyzed for significance together.

No statistical comparisons by group were reported.

The remainder of the 32 studies evaluated insomnia symptoms in patients with cancer,^43,55,57 multiple sclerosis and other neurological diagnoses,^{34,35,39,42,46,52,56,60,61} psychiatric disorders,^40,59 chronic pain,^{36,37,51,53,58} autoimmune hepatitis,⁴⁹ brachial plexus injury,³¹ rheumatoid arthritis,³² fibromyalgia,³³ cannabis/CBD users,^22,38,41,62 and healthy adults.^44,47,50,54 Insomnia was the primary outcome in 10 studies^{30,32,35,45,47,49,50,54,59,62} and a secondary outcome for the remaining 24 studies. Other primary outcomes included pain,^{31,32,36–38,41,43,46,53,55,56,58,60,61} spasticity,^39,52,60,61 mobility,⁴¹ anxiety and other psychiatric disorders,^{30,38,40,41,54,62} fatigue/sleepiness,^49,50 urinary tract symptoms,^34,39 safety/tolerability of CBD/cannabis use,^33,42,51 and reasons for CBD/cannabis use.^22,33,44,48

Sleep measures and outcomes

Studies utilized a variety of sleep outcomes related to insomnia, including number of sleep disturbances per night,^{30,31,35,42,52,53,55,56} sleep quality,^{31,32,36,39,40,43,44,46,57–61} ability to fall asleep or stay asleep,^22,35,47,50 and total sleep duration^47,50,61 (Table 3). All but two studies^47,50 used subjective self-report questionnaires such as numeric rating scales,^{31,32,35,38,39,42,43,46,52,55,56,58} Likert scales,³³ visual analog scales,^34,60,61 purpose-developed survey questions,^44,49 the Pittsburgh Sleep Quality Index,^36,59 or specific questions within questionnaires such as the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire.^35,40,43,57 Two studies^47,50 utilized polysomnography to objectively measure CBDs impact on sleep outcomes. However, the participants in both studies were healthy adults with no preexisting insomnia symptoms.

CBD preparations and usage

Nineteen studies investigated the effects of CBD monotherapy/predominant therapy on insomnia symptoms (seven cross-sectional studies,^{22,33,35,37,44,48,49} four cohort studies,^36,38,41,45 four clinical trials,^42,47,51,60 three case series,^40,54,59 and one case report³⁰) (Table 3). Twenty-one studies investigated the effects of products with nearly equal ratios of CBD to THC (17 clinical trials,^{31,32,34,39,42,43,46,50–53,55–58,60,61} 2 cross-sectional studies,^35,37 and 2 cohort studies^38,62). CBD-containing products were administered through various routes, including oromucosal or sublingual sprays/drops,^{31,32,34,39–41,43,44,46,49–56,58,60,61} oral capsules/gelatine,^{40,44,47,49,59} inhalation,^38,49 or topical application⁴⁹ with varying dose and frequency. For studies that reported the quantity of CBD used, doses ranged from 2.5 mg of CBD to 330 mg daily.

Effects of CBD on insomnia symptoms

All the 34 studies reported some level of improvement in the insomnia symptoms of at least a portion of their participants following the administration of CBD-containing products (Table 3). Of the 19 studies that investigated the effects of CBD monotherapy/predominant therapy on insomnia symptoms, 7 studies^{36,42,45,47,51,54,60} tested for significant versus insignificant improvement compared with baseline or placebo. Four of these studies reported statistically significant improvements in insomnia symptoms (two cohort studies,^36,45 one case series,⁵⁴ and one clinical trial⁵¹). Of the 21 studies that investigated the effects of products with nearly equal ratios of CBD to THC, 16 studies^{31,32,34,39,42,43,46,50–53,55,56,58,60,61} tested for significant versus insignificant improvement compared with baseline or placebo. Twelve of these studies reported statistically significant improvements in insomnia symptoms (12 clinical trials^{31,32,42,46,51–53,55,56,58,60,61}).

Risk of bias

A similar number of studies had low versus high risk of bias (Table 5). Overall, 16 studies had a low risk of bias (15 clinical trials^{31,32,39,43,46,47,50,52,53,55–58,60,61} and 1 cross-sectional study³³), 4 studies had a moderate risk of bias (2 case series/case reports,^30,59 1 cohort study,⁴⁵ and 1 clinical trial⁵¹), and 14 studies had a high risk of bias (6 cross-sectional studies,^{22,35,37,44,48,49} 4 cohort studies,^36,38,41,62 2 case series/case reports,^40,54 and 2 clinical trials^34,42). Common problems among studies with cohort designs included not attempting to balance the allocation between the groups, not selecting an appropriate comparison group, and not having similar baseline characteristics between the groups.

Table 5.

Risk of Bias of Individual Studies Using the Agency for Healthcare Research and Quality Design-Specific Recommended Criteria

Study design, first author (year)	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Q9	Q10	Q11	Q12	Q13	Q14	Q15	Q16	Q17	Q18	Q19	Q20	Total	Percent	Risk of bias
Clinical trials
Berman (2004)³¹	1	1	—	—	—	1	1	—	1	1	—	1	1	1	1	1	1	1	—	1	14	100	Low
Blake (2006)³²	1	1	—	—	—	0	1	—	1	1	—	1	0	1	1	1	1	1	—	1	12	85.7	Low
Collin (2010)³⁹	0	0	—	—	—	1	1	—	0	1	—	0	1	1	1	1	1	1	—	1	10	71.4	Low
Johnson (2010)⁴³	1	0	—	—	—	1	1	—	1	1	—	0	1	1	1	1	1	1		1	12	85.7	Low
Langford (2013)⁴⁶	1	1	—	—	—	1	1	—	1	1	—	1	1	1	1	1	1	1	—	1	14	100	Low
Linares (2018)⁴⁷	1	1	—	—	—	1	1		1	1	—	1	1	0	1	1	1	1		1	13	92.9	Low
Nicholson (2004)⁵⁰	0	0	—	—	—	1	1		1	1	—	1	1	1	0	1	1	1	—	1	11	78.6	Low
Novotna (2011)⁵²	1	1	—	—	—	1	1	—	1	1	—	0	1	0	1	1	1	1	—	1	12	85.7	Low
Nurmikko (2007)⁵³	1	1	—	—	—	1	1	—	1	0	—	0	0	1	1	1	1	1	—	1	11	78.6	Low
Portenoy (2012)⁵⁵	1	1	—	—	—	1	1		1	1	—	0	0	1	1	1	1	0	—	1	11	78.6	Low
Rog (2005)⁵⁶	1	1	—	—	—	1	1	—	1	0	—	1	1	1	1	1	1	1	—	1	13	92.9	Low
Schloss (2021)⁵⁷	1	1				1	1	—	0	1	—	0	0	1	1	1	1	1	—	1	11	78.6	Low
Serpell (2014)⁵⁸	1	1	—	—	—	1	1	—	1	1	—	1	1	1	1	1	1	1	—	1	14	100	Low
Wade (2003)⁶⁰	1	1	—	—	—	1	1	—	1	1	—	1	1	0	1	1	1	1	—	1	13	92.9	Low
Wade (2004)⁶¹	1	1	—	—	—	1	1	—	1	1	—	1	1	0	1	1	1	1	—	1	13	92.9	Low
Notcutt (2004)⁵¹	1	1	—	—	—	1	1	—	0	0	—	1	1	0	1	0	1	0	—	1	9	64.3	Moderate
Brady (2004)³⁴	0	0	—	—	—	1	1	—	0	1	—	0	0	0	0	1	1	1	—	0	6	42.9	High
Gustavsen (2021)⁴²	0	0	—	—	—	1	0	—	0	0	—	0	0	0	0	1	1	0	—	1	4	28.6	High
Cross sectional
Boehnke (2021)³³	—	—	—	—	—	—	—	0	0	—	—	—	1	—	1	1	1	1	1	1	7	77.8	Low
Braley (2020)³⁵	—	—	—	—	—	—	—	0	0	—	—	—	1	—	0	1	1	1	0	1	5	55.6	High
Carrubba (2021)³⁷	—	—	—	—	—	—	—	0	0	—	—	—	1	—	0	1	1	1	0	1	5	55.6	High
Kasper (2020)⁴⁴	—	—	—	—	—	—	—	0	0	—	—	—	1	—	0	1	0	0	0	1	3	33.3	High
Lovecchio (2021)⁴⁸	—	—	—	—	—	—	—	0	0	—	—	—	1	—	0	1	0	0	0	1	3	33.3	High
Mathur (2020)⁴⁹	—	—	—	—	—	—	—	0	0	—	—	—	1	—	0	1	1	0	1	0	4	44.4	High
Moltke (2021)²²	—	—	—	—	—	—	—	1	0	—	—	—	1	—	0	0	0	0	0	1	3	33.3	High
Cohort
Kuhathasan (2021)⁴⁵	—	—	0	1	0	1	0	0	0	1	1	1	1	0	1	1	1	1	1	1	12	66.7	Moderate
Capano (2020)³⁶	—	—	0	1	0	1	0	0	0	1	1	0	0	0	0	1	1	1	0	1	8	44.4	High
Casarett (2019)³⁸	—	—	0	1	1	1	0	0	0	0	1	1	1	0	0	0	1	1	0	1	9	50	High
Gulbransen (2020)⁴¹	—	—	0	1	0	1	0	0	0	0	1	0	0	0	0	1	1	1	0	1	7	38.9	High
Wan (2017)⁶²	—	—	0	0	0	1	0	0	0	0	1	0	0	0	0	0	0	0	0	1	3	16.7	High
Case series/case report
Shannon (2019)⁵⁹	—	—	—	—	—	—	—	0	0	1	—	—	1	—	0	1	1	1	0	1	6	60	Moderate
Berger (2020)³⁰	—	—	—	—	—	—	—	0	0	1	—	—	1	—	0	1	1	1	0	1	6	60	Moderate
Elms (2019)⁴⁰	—	—	—	—	—	—	—	0	0	1	—	—	0	—	0	1	1	1	0	1	5	50	High
Pacheco (2021)⁵⁴	—	—	—	—	—	—	—	0	0	0	—	—	1	—	0	1	1	1	0	1	5	50	High

Articles with a score less than 60% of the highest possible score are designated as high risk of bias; articles with a score 60%–69.9% of the highest possible score are designated as moderate risk of bias; articles with a score greater than or equal to 70% of the highest possible score are designated as low risk of bias.

—Signifies that question is not relevant to the study design; 1 signifies desirable, low risk of bias answer to question; 0 signifies undesirable, high risk of bias answer to question (including “unsure”). Questions can be found in Table 2.

Additionally, only clinical trials addressed the impact from concurrent interventions or unintended exposure that might bias results. Thirteen studies^{22,30,35–38,40,41,44,48,54,59,62} did not assess confounding variables using valid and reliable measures. Seventeen studies^{22,30,34–38,40–42,44,48–50,54,59,62} did not have outcome assessors blinded to the intervention or exposure status of participants. Attrition was also a potential problem for 19 studies.^{32,34,36,38–43,45,47,51–53,55,57,60–62}

Discussion

The results of this systematic review suggest that CBD, either alone or in combination with equal amounts of THC, may be beneficial in the management of comorbid insomnia in patients with cancer, multiple sclerosis, psychiatric disorders, chronic pain, and PTSD. However, because only two included studies focused on patients with insomnia (including one case report), these results cannot be generalized to patients with primary insomnia.

Our results are consistent with previous reviews examining the effects of CBD on sleep outcomes. For example, a systematic review by Khan et al⁶³ examined the therapeutic benefits of CBD in psychiatric disorders and reported that CBD may be beneficial in patients with insomnia related to seasonal affective disorder and PTSD. However, based on the level of evidence, the authors graded their recommendation for the use of CBD for insomnia as weak. The results of another systematic review that evaluated the use of THC alone or THC in combination with CBD for sleep outcomes in patients with multiple sclerosis, PTSD, and chronic pain also concurred with the results of our study.²⁷ However, the authors reported several shortcomings, including a dearth of studies in which sleep was the primary outcome and the use of nonvalidated questionnaires to measure sleep outcomes.

Although the initial goal of this review was to exclusively evaluate CBD (and not THC) for insomnia, it became clear following our literature searches that there were few clinical studies with CBD alone that included sleep as an outcome. Consequently, we elected to include all studies that had a treatment arm with CBD in equal or higher concentration compared with other cannabinoids. This decision resulted in the inclusion of studies with nabiximols (which have a nearly equal ratio of THC to CBD). In these studies, it is difficult to differentiate the specific effects of CBD versus THC, and nabiximols require further study.

For example, high doses of CBD have been shown to be sedative while also being nonintoxicating and having a low addiction risk.⁶⁴ THC, however, is psychoactive and with chronic use may decrease sleep latency, interfere with the circadian sleep–wake cycle, reduce somnolence (while increasing daytime sleepiness and delaying sleep onset the next night), and decrease slow-wave sleep.^24,64,65 However, given that the 12 studies using nearly equal ratios of CBD to THC found significant improvements in insomnia outcomes, it is possible that CBD balances the effects of THC on sleep and the combination of the 2 cannabinoids may be synergistic for insomnia.

Study limitations

Our study had several limitations. First, only three clinical trials in this systematic review investigated CBD monotherapy/predominant therapy, and none of these three studies were conducted in patients with insomnia (one focused on healthy adults, one on patients with neurological diagnoses, and one on patients with chronic pain). Second, only 1 study⁵⁰ of the 34 studies reported being specifically powered to detect insomnia-related outcomes. Third, the majority of the studies lacked objective measures of insomnia, and several studies used nonvalidated instruments to measure insomnia symptoms. Fourth, there was a high degree of variability in outcomes and treatments. Finally, nearly half of our included studies had a high risk of bias.

Conclusions

Despite these limitations, the results of our systematic review suggest that CBD (alone or in combination with THC) may be helpful in managing insomnia symptoms. Additional studies examining the effects of CBD in patients with insomnia are needed, particularly studies that use validated subjective and objective measures to assess insomnia, before CBD can be strongly recommended in clinical practice.

Availability of Data and Material

The data supporting the conclusions of this article are available from the corresponding author upon request.

Footnotes

Acknowledgments

The authors would like to acknowledge Mayo Clinic Librarians Leslie Hassett, MLS, and Julie Taylor, MLS, for their valuable help in conducting literature searches for this systematic review.

Authors' Contributions

R.M.R., M.O.W., L.L.T., and A.V. were responsible for the conception and design of the work. R.M.R., M.O.W., and A.V. were responsible for the acquisition and interpretation of data. All authors were involved in drafting the article, critically revised it for intellectual content, and approved the final version of the article.

Author Disclosure Statement

No competing interests have been declared by the authors.

Funding Information

No funding was received for this systematic review.

Abbreviations Used

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