Abstract Chronic pain affects 35-40% of people with chronic neurological conditions, including persons with multiple sclerosis (MS) - an autoimmune disease of the central nervous system affecting approximately 1 million Americans. Unfortunately, the analgesic effects of conventional treatments for pain in neurological conditions is limited. Cannabidiol (CBD, derived from cannabis sativa) is a safe, promising complimentary therapy that is frequently used in combination with Δ-9-tetrahydrocannabinol (THC) to treat pain in persons with MS (PwMS). However, the distinct analgesic mechanisms of CBD - relative to better-studied cannabinoid formulations such as THC or THC/CBD combinations (which carry abuse potential) - are not well understood, galvanizing the need for mechanistic research focused on CBD monotherapy. Preliminary data from a nationwide study of PwMS conducted by the investigators suggest that CBD could independently exert analgesic effects through improved sleep, particularly among PwMS with nociplastic (centralized) pain. Investigations that now build upon these early findings could provide novel insight into mechanisms by which CBD induces analgesic effects, and identify pain phenotypes that are most likely to be responsive to CBD for chronic pain. This innovative, mechanistic study proposes to apply novel polysomnographic sleep stage analyses that extend beyond conventional polysomnography (PSG) measures, and new features of sleep macrostructure derived from in-home actigraphy, to assess aspects of sleep that could play key mechanistic roles in the analgesic effects of CBD. Our overarching goal is to apply these novel sleep assessment methods, coupled with validated pain phenotyping techniques, to uncover unique mechanistic associations between CBD, sleep, and analgesia in PwMS, compared to THC monotherapy, THC/CBD combination therapy, or placebo. Persons with MS who experience chronic pain will undergo pain phenotyping with validated survey measures of nociplastic and neuropathic pain, and randomized to CBD (Epidiolex®), THC (dronabinol), THC/CBD combination, or placebo for 12 weeks. In-lab PSG and 14-day wrist-worn actigraphy will be collected at baseline and 12 weeks’ post-treatment. Changes in sleep microstructure (Aim 1; including sleep stage bout length, sleep stage transition probability, and entropy) and macrostructure (Aim 2; including sleep regularity, rhythmicity, timing and duration) will be compared between cannabinoid and placebo groups, and pain phenotype will be assessed as a predictor of CBD-related changes in sleep. Aim 3 will assess the measures of sleep microstructure and macrostructure as mediators of analgesic response to CBD. Data generated from this study will to inform CBD research, across a spectrum of neurological and other chronic conditions, that can be applied to the development of precision-medicine approaches for chronic pain.