A survey-based, quasi-experimental study assessing a high-cannabidiol suppository for menstrual-related pain and discomfort

This is the first study to assess the impact of a “real-world”, commercially-available, high-CBD suppository on menstrual-related pain and discomfort, and extends prior work suggesting MC has promising potential for alleviating menstrual-related symptoms^17,18,19. Previous survey studies have reported MC use significantly reduced pain, cramping/muscle spasms, mood, anxiety, sleep, and gastrointestinal issues as well as improved quality of life in participants with PMS/PMDD³², endometriosis^33,34, chronic pelvic pain^35,36, and menopause³⁷. Results from the current study indicate that participants who used high-CBD suppositories PRN for menstrual-related pain and discomfort demonstrated significantly greater improvement in their symptoms over two months relative to TAU participants. For the majority of symptoms, both frequency and severity of symptoms as well as the impact of symptoms on daily functioning were more significantly reduced relative to the TAU group, and in the CBD group, the majority of participants perceived at least moderate improvement of symptoms. Analyses of symptom types suggest that CBD suppositories may be more effective for congestive (i.e., dull, aching pains accompanied by energy and mood symptoms) rather than spasmodic symptoms (i.e., sharp spasms of pain). When considering symptoms at various phases of the menstrual cycle, the CBD group demonstrated greater symptom improvement relative to the TAU group for all symptom types during menstruation except for arousal/energy; improvement of premenstrual symptoms was also noted for behavioral changes and autonomic reactions.

Previous work suggests CBD may address pain and inflammation associated with dysmenorrhea¹⁹, endometriosis^20,21,22, and chronic pelvic pain²³, and observational studies indicate that MC use may help reduce the use of conventional medications, particularly analgesics^26,33. In the current study, the CBD group reported significantly greater reductions of pain during menstruation, need for analgesics, and number of analgesic pills taken relative to the TAU group. Importantly however, while NRS ratings of pain severity decreased significantly over time for all participants (i.e., main effect of time), the LMM analyses did not differentiate the two groups (i.e., group*time interactions were not significant). Notably, the NRS used in the current study was a 0–10 rating for average and worst menstrual pain, which while important, is a fairly general assessment, and more comprehensive, specific assessments of pain-related symptoms (e.g., VMS, RSS, MDQ) did in fact differentiate the groups, underscoring the importance of utilizing subscales assessing a range of specific symptoms. Additionally, the CBD group did report significant improvement on the impact of menstrual-related symptoms on life (e.g., avoiding activities) as well as reduced use of analgesics, which may indicate that even though pain severity ratings did not differ by group, management of pain (e.g., need for analgesics, impact on daily functioning) was significantly improved in the CBD group relative to the TAU group. Taken together, these results suggest that cannabinoid-based therapies may help to treat menstrual-related symptoms and reduce use of conventional analgesics.

Correlations indicated a potential dose-dependent response, with increased suppository use significantly associated with greater symptom reduction, improved daily functioning, and reduced need for analgesics. These analyses suggest suppository use may be most effective during menstruation, particularly for addressing and managing pain, water retention, and negative affect. While correlations for premenstrual symptoms did not reach statistical significance, most participants reported suppository use during menstruation; only about half reported use during the premenstrual phase. Exploratory correlations utilizing a subset of participants who reported using suppositories during their premenstrual phase indicated that suppository use significantly correlated with improvements in premenstrual behavioral changes (p = 0.042, Table 5). These findings suggest the statistical power for analyses of premenstrual symptoms was likely reduced given fewer participants used suppositories during this phase.

Given expanding legalization and availability of MC products, increasing numbers of individuals are exploring MC to alleviate symptoms of a variety of medical conditions⁴⁸. Estimates suggest ~13–23% of patients with gynecological conditions (e.g., endometriosis, pelvic pain) use MC to alleviate symptoms^33,35. However, cannabinoid-based therapies may not be appropriate for all gynecological indications. For example, increased serum AEA and decreased endometrial FAAH expression may accelerate the progression of PCOS¹. Additionally, ECS function in the gynecological system is impacted by aging⁴⁹, suggesting the potential for differential impacts of cannabinoid-based therapies with age, which should also be explored. Further, exogenous cannabinoids, including CBD, interact with cytochrome P450 enzymes involved in hepatic metabolism, which may result in drug-drug interactions with other medications^50,51,52. Caution is warranted for patients taking medications with a narrow therapeutic index (i.e., the ratio between a drug’s toxicity and effectiveness) including some anticoagulants, beta blockers, antidepressants, and antipsychotics. Importantly for the current study, the use of a transmucosal route of administration, with drug absorption occurring through the vaginal mucosa, bypasses first-pass hepatic metabolism which may reduce the risk of potential side effects and drug-drug interactions⁵³.

Previous research has identified several potential sources of ECS dysfunction associated with gynecological conditions and symptoms, including altered expression of ECS genes¹¹, receptors^14,15,16, and synthesizing/degrading enzymes^12,13. However, more work is needed to identify the specific mechanism(s) of action for cannabinoid-based therapies as well as the most efficacious cannabinoid constituent profiles, dosing strategies, and product types in order to inform clinical practice. Future randomized, placebo-controlled, clinical trials are warranted to determine safety and efficacy for various gynecological conditions and symptoms.

Additionally, some question the use of vaginal applications of cannabinoid-based medicines given concerns regarding absorption, controlled release, and whether cannabinoids reach the uterus using suppositories as a delivery system¹⁹. Current results provide preliminary evidence that vaginal suppositories can be an effective route of administration for cannabinoid-based therapies; however, future work should evaluate the impact of different routes of administration, including pharmacokinetic/pharmacodynamic analyses.

This study had several strengths and limitations. A survey-based, quasi-experimental study design without prospective group assignment was necessary given restrictions prohibiting the use of commercially-available products in clinical trials in the US. In order to conduct a clinical trial of a CBD-containing product, the product must be studied under an Investigational New Drug (IND) application; this means it would be illegal for a product to simultaneously be for sale in the marketplace while being studied under an IND, as it would be considered an unapproved drug⁵⁴. Importantly, within the US, hemp-derived products, defined as those containing ≤0.3% THC by weight, are federally legal⁵⁵, which has resulted in thousands of commercially-available “low THC” or “THC-free” products flooding the marketplace without any ability to study their impact using standard clinical trial models. As there is a paucity of data assessing the efficacy of these commercially-available, “real world” products, investigations like the current study provide critical information that is otherwise unavailable.

While randomized, controlled clinical trials have the highest level of scientific rigor for assessment of causality, when randomization of the intervention is not possible (i.e., due to federal restrictions) or unethical, non-randomized, quasi-experimental studies are typically the most rigorous option⁵⁶. Accordingly, the current study assessed the efficacy of individuals’ naturalistic (i.e., PRN) use of a commercially-available CBD suppository for menstrual-related symptoms, with participants providing information regarding suppository use. Correlation analyses further strengthened study findings, providing evidence for a potential dose-dependent response to suppository use. Additionally, since the CBD suppositories are commercially-available in the US and cannot be used as part of a clinical trial, participants were required to deal directly with the manufacturer/study sponsor regarding all issues related to the receipt and use of the product; the research team could not have any clinical interaction with study participants. As a result, individuals were instructed to direct concerns regarding suppository use directly to the sponsor, and no information regarding side effects or adverse events was collected by the research team. Information about the safety profile and potential side effects (i.e., lowered blood pressure, light-headedness, drowsiness, dry mouth) of these suppositories was readily available in the Health, Safety, and Ingredients section of the sponsor’s website³⁸, which also includes links to Certificate of Analyses for all of their products.

Notably, the CBD group reported significantly greater menstrual-related symptomatology at baseline relative to the TAU group, which aligns with previous work demonstrating that poorer health and inadequate symptom relief with conventional treatment are associated with utilizing alternative treatment strategies such as MC⁵⁷. To account for significant between-group differences at baseline, autoregressive LMM were utilized; interestingly, post hoc analyses revealed no significant between-group differences at either follow-up, suggesting the more severe baseline symptom presentation was eliminated by the use of the CBD suppositories.

Additionally, previous research has also demonstrated differential efficacy of over-the-counter (OTC) analgesics for dysmenorrhea. A recent meta-analysis identified ibuprofen as the optimal OTC analgesic for dysmenorrhea with the best efficacy and safety profile; whereas aspirin (acetylsalicylic acid) was no more effective than placebo⁵⁸. While information regarding analgesic use and effectiveness was collected for this study via well-validated clinical scales (e.g., VMS, RSS), comprehensive information regarding participants’ individual analgesic regimens was not collected. Therefore, baseline between-group differences may have been related to greater prevalence of ineffective analgesic use within the CBD group. However, even if the CBD group had a higher prevalence of ineffective analgesic use at baseline, the significant improvement of symptoms within this group is still notable. Future research should investigate the potential impact of CBD suppositories on the efficacy of conventional analgesics.

Further, observational studies of MC use for gynecological symptoms have demonstrated that treatment expectancies can significantly mediate self-reported outcomes^32,59. Unfortunately, treatment expectancies were not directly assessed in the current study. However, while well-validated metrics exist to assess expectancies related to recreational cannabis use (e.g., Marijuana Effect Expectancy Questionnaire⁶⁰), no validated metrics were available to asses MC treatment expectancies. Future work should include measures of treatment expectancy specifically designed for MC use.

The racial distribution of the current study is similar to the most recent US census⁶¹, suggesting good sampling and high generalizability. Notably, participants were not required to be cannabis-naïve at baseline. While additional cannabis use likely impacted results, rates of current cannabis use were not significantly different between treatment groups. Further, given increased prevalence of MC use for gynecological symptoms^33,35 and evidence that individuals who have previously tried/used cannabis are more likely to use MC to address gynecological symptoms⁶², requiring participants to be cannabis-naïve would not accurately reflect this clinical population. Future studies should use a comprehensive metric (e.g., CannaCount⁶³) to assess and control for additional cannabis use.

In conclusion, although dysmenorrhea is quite common, the current study is the first preliminary study to assess a “real world”, high-CBD vaginal suppository for menstrual-related pain and discomfort. Findings suggest these suppositories alleviated a range of menstrual-related symptoms, improved daily functioning, and reduced use of analgesics. Increased suppository use was significantly associated with greater reduction of symptoms, suggesting a potential dose-dependent response. Current study results expand previous preclinical and observational findings; future studies should replicate and expand current findings and further examine the pharmacokinetics and pharmacodynamics, mechanism(s) of action, efficacy for other gynecological indications, and potential for adverse events (e.g., drug-drug interactions), ultimately using clinical trial models.