Evaluating the effect of cannabidiol on sleep quality in patients with multiple sclerosis using 15 aggregated N-of-1 trials: A study protocol

Background: Sleep disorders, including insomnia, are highly prevalent in individuals with multiple sclerosis (MS), significantly impacting quality of life. Patients frequently use cannabidiol (CBD) as an alternative to standard medical treatments for sleep disorders, yet its efficacy has not been rigorously investigated. Methods: This study comprises 15 randomized, placebo-controlled N-of-1 trials evaluating the effect of pure CBD oil (10 % g/v) on sleep quality in MS patients. Each N-of-1 study consists of a two-week run-in period, followed by four treatment periods of three weeks, separated by a one-week washout. Participants receive both CBD and placebo twice in a randomized order. Treatment starts at 150 mg daily, increasing to 300 mg from week 2. Study outcomes are assessed during the final two weeks of each block. The primary outcome is sleep quality, measured by the Insomnia Severity Index (ISI). Secondary outcomes include patient-reported outcome measures of sleep recorded in a sleep-wake diary, and scores on the Checklist Individual Strength Fatigue-subscale (CIS-F), the Fatigue Severity Scale (FSS), and the Epworth Sleepiness Scale (ESS). Additionally, as a continuous proxy for fatigue, smartphone keyboard interactions will be collected using the Neurokeys application. Results from the individual N-of-1 trials will be aggregated for group-level analyses. Discussion: This study aims to provide insight into the effects of a controlled CBD product on sleep quality in MS patients through an N-of-1 trial design. Given the substantial variability in sleep quality and the anticipated interindividual differences in CBD response, an N-of-1 design is considered a suitable methodological approach.