(161) CBDA and CBD Diminish Spontaneous Contractions of the Myometrium in vitro and Significantly Ameliorate Pain in Primary Dysmenorrhea

Abstract Introduction Primary Dysmenorrhea (PD), painful uterine menstrual cramps occurring in the absence of identifiable pelvic pathology and it has been linked to excess prostaglandin PGF₂α and PGE₂ production in the endometrium and myometrium leading to increased uterine contractility, vasomotor constriction, and ischemic pain. Objective We (1) examined the ability of cannabidiolic acid (CBDA) and cannabidiol (CBD) to diminish the intensity and frequency of spontaneous rat myometrial contractions and (2) a proof of concept (PoC) clinical study of a combination CBDA and CBD intravaginal suppository in women with PD to ameliorate pain. Methods (1) The relaxant effects of Cannabidiolic Acid (CBDA) and Cannabidiol (CBD) were first investigated in an ex vivo model using myometrial strips isolated from the uterine horns of non-pregnant, estrus-stage female Sprague–Dawley rats (n = 14). The strips were mounted in organ bath chambers to measure isometric tension and assess the compounds’ impact on spontaneous myometrial contractions. (2) Subsequently, an IRB-approved, single-cycle clinical trial was conducted with 48 women, aged 21-35, who had lifelong, mild-to-severe dysmenorrhea. Participants self-administered an intravaginal suppository containing 25 mg CBDA and 75 mg CBD, 1-2 times daily from the onset of pain and for its duration. The therapeutic effect was evaluated using a 10-point composite pain scale that integrated pain intensity with the use of oral analgesics, with scores compared from a pre-pain baseline to the end of the menstrual cycle: Results In the preclinical investigation, both CBD and CBDA demonstrated a significant and concentration-dependent (1, 10, and 100 μg/mL) relaxant effect on the amplitude and frequency of spontaneous contractions in rat uterine horn strips compared to vehicle. CBDA was found to be significantly more potent than CBD in reducing contraction amplitude (p 0.001, two-way ANOVA; Fig. 1). In the clinical proof-of-concept study, analysis of the participant population revealed a significant reduction in dysmenorrhea pain. The total cohort (n = 48) showed a decrease in the mean pain score from a baseline of 6.38 to 3.54 at the end of the study, constituting a 44.4% reduction that was statistically significant (p 0.0001). A subpopulation of women who began with mild pain or whose moderate pain shifted to mild (baseline score: 5.43) exhibited an even more pronounced effect, achieving a mean end-of-study score of 1.71, which reflects a 68.4% reduction in pain (p 0.0001; Fig. 2). Corroborating these findings, 81% of participants reduced their use of oral analgesics. The treatment regimen was well-tolerated, with the most common adverse event being leakage and no serious adverse events reported. The majority of participants used one suppository nightly for five days, and most indicated a willingness to use the product again for future menstrual cycles. Conclusions An intravaginal CBDA and CBD suppository statistically and clinically significantly reduces pain in Primary Dysmenorrhea through the reduction in the intensity of uterine contractions. CBDA is a critical component of this effect due to its greater potency in reducing the amplitude (intensity) of myometrial spontaneous contractions. Disclosure Yes, this is sponsored by industry/sponsor: Vella Bioscience, Inc. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Vella Bioscience, Inc.