PAIN: Project Assessing the Mechanisms and Impact of a Novel Cannabinoid Product - ABSTRACT Over 1.5 billion women worldwide suffer with gynecologic disease, with pain as a primary symptom. Despite its prevalence, gynecologic pain is highly undertreated and understudied and effective treatment options remain limited. As a result, many women are interested in alternative treatment options, including medical cannabis. Given its purported therapeutic properties, many specifically turn to products containing cannabidiol (CBD), the primary non-intoxicating constituent in cannabis, to alleviate pain, as well as comorbid symptoms of anxiety and depression. Although CBD treatments for pain hold promise, studies conducted thus far have yielded mixed results, and potential mechanisms of action remain unknown. Previous studies have suggested that CBD has analgesic and anti-inflammatory actions and can modulate the endocannabinoid system (ECS), a neuromodulatory system that includes endogenous cannabinoids such as anandamide (AEA) which is also implicated in analgesia and anti-inflammatory processes. Accordingly, this two-phase, milestone-driven project will assess the impact of a high-CBD (250 mg/mL), full-spectrum product containing additional minor cannabinoids and terpenes optimized for pain on two primary targets – inflammatory markers (e.g. CRP, IL-1B, IL-6, TNF-α) and AEA – and ultimately, measures of clinical outcome in those with gynecologic pain. The R61 phase will include PK studies of two doses of the study product at baseline and following 7 days of study drug administration (Aim 1; n=up to30). Changes in primary targets (inflammatory markers, circulating AEA) will be measured at baseline and post-7 days (Aim 2), and the impact of two active doses (350 mg/day vs 750 mg/day) on target engagement will be assessed relative to placebo (Aim 3) in up to 60 participants. The R61 will also include an evaluation of pain sensitization as a phenotype in gynecologic pain that may modulate the effects of the high-CBD product. If the high-CBD product is found to be superior to placebo in target engagement, the R33 phase will attempt to replicate and extend initial findings by comparing the most effective dose identified in the R61 phase to placebo in up to 60 patients using a 6-week, randomized, double-blind, clinical trial (Aim 1). The relationship between target engagement and clinical outcomes (assessment of pain, comorbid symptoms of anxiety and mood) will also be assessed (Aim 2). This innovative proposal which aims to identify the potential role for a high-CBD, full-spectrum product and evaluate safety/tolerability will have a significant public health impact regardless of the outcome, in light of the prevalence of women with gynecologic pain who turn to products with no empirical evidence given a lack of effective treatment options. Importantly, positive findings are likely to facilitate development of a safe, effective alternative treatment strategy for gynecological pain, which may be generalizable to other chronic pain conditions. If successful, findings from the current study could serve as the foundation for future studies and larger scale, multi-site clinical trials, paving the way for alternative treatments for millions suffering from debilitating conditions.
