Abstract
Introduction:
Endometriosis is a chronic condition that affects millions of women in the United States. Chronic pain can be debilitating and complex to manage. Despite common approaches like hormonal treatments and surgery, many women continue to endure pain. Managing the chronic and multifaceted nature of endometriotic pain necessitates a comprehensive strategy.
Methods:
This study explores the potential of cannabis in alleviating endometriosis-related pain through an extensive literature search. Cohort studies, case-control studies, cross-sectional surveys, and systematic reviews from January 1996 to August 2022 were eligible for inclusion. Articles were then assessed and included for further analysis if they met the following criteria: (1) Population was women with endometriosis; (2) Discussed the therapeutic use of medical cannabis for endometriosis-related pain.
Results:
The literature search revealed 522 articles, with eight articles meeting criteria for analysis: four cross-sectional surveys, two systematic reviews, one retrospective cohort study, and one literature review. Cannabis consumption for symptom relief was common among women with endometriosis, and some even reported that the use of cannabis reduced their use of analgesics.
Discussion:
The use of cannabis for endometriosis-related pain holds significant promise for addressing the often-debilitating comfort experienced by those with this condition. By interacting with the endocannabinoid system, cannabis may provide relief by modulating pain perception, reducing inflammation, relaxing muscles, and alleviating neuropathic discomfort.
Background
Endometriosis is a common, chronic inflammatory gynecological condition that affects approximately 6.5 million women in the US and 190 million women worldwide. 1 It is characterized by the presence of endometrial-like tissue found outside the uterus. Endometriosis causes a myriad of symptoms such as chronic pelvic pain, dyspnea, dyspareunia, dyschezia, and dysuria. Management of the chronic and life-limiting health implications of endometriosis has been associated with decreased quality of life among women coping with this disease. 2 Typical management of endometriosis often includes prescription and nonprescription analgesics, oral contraceptives, laparoscopy, and in some cases hysterectomy. 3 Despite its prevalence, there is no cure for this chronic illness. Furthermore, traditional treatment options are limited and have come with adverse effects, which has resulted in a growing interest in alternative approaches for effective pain management. In recent years within the United States, there has been a surge in cannabis legalization for various medical conditions, including chronic pain management. 4 Specifically, medical cannabis refers to the use of the marijuana plant and its derivatives for therapeutic purposes under the guidance of a medical professional. Growing access to medical marijuana, along with the analgesic and anti-inflammatory properties of cannabinoids, has sparked interest in the role of cannabinoids in alleviating endometriosis-related pain.
However, the relationship between medical cannabis and endometriosis-related pain remains unclear. A comprehensive analysis and evaluation of the current evidence is necessary to determine the next steps needed to advance scientific knowledge regarding the relationship between cannabis use and management of endometriosis-associated pain. The current perspective presents our review of the literature on cannabis and the management of endometrial-associated pain and outlines the next steps in this line of research, with a model for how and why cannabis should be examined as a first-line treatment for the management of endometriosis-related pain.
Methods
Prior to starting our review, this protocol was registered with PROSPERO (Registration # CRD42022353816). The literature for this review was collected from the following databases: PubMed, Web of Science, Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We included the following terms in our electronic search strings: MeSH and other database-specific subject headings, synonym keyword terms and phrases, and a partially validated search filters5–7 The search was designed by a health sciences librarian, and peer review of the search was conducted by a second health sciences librarian using the Peer Review of Electronic Search Strategies checklist and form. This search included only human subject research studies. We excluded animal research studies from the searches using a partially validated search filter when appropriate for the database. We also restricted our searches to only include English-language studies published after January 1, 1996. Searches were run in each database and exported into an EndNote library. All search results were then uploaded into Covidence and deduplicated upon importation. We used Covidence to organize, screen, review, and extract data from the unique references retrieved in the searches.
Cohort studies, case-control studies, cross-sectional surveys, and systematic reviews from January 1996 to August 2022 assessing any relationship between cannabis use and endometriosis were eligible for inclusion. Retrieved articles were independently reviewed by two reviewers and any discrepancies were resolved by consensus with a third reviewer. Suitable articles were assessed to see if they met the following criteria: (1) Population was women with endometriosis; (2) Discussed the therapeutic use of medical cannabis for endometriosis-related pain.
Results
A total of 522 references were identified and retrieved. Following screening, eight articles were included for review: four cross-sectional surveys, two systematic reviews, one retrospective cohort study, and one review of literature (Table 1). Across five of the studies, 1817 total participants were found to have used cannabis for endometriosis symptom management. All included studies were from countries where cannabis is legalized medicinally and/or recreationally.
Characteristics of Included Studies
Self-reported cross-sectional survey data suggests that cannabis is beneficial for management of endometriosis-related pain. Cross-sectional survey data currently constitutes the bulk of the available scientific evidence in this domain to date and has largely been collected by the same researchers. Survey data of self-management strategies among women with endometriosis showed that cannabis use was reported with the greatest effectiveness for alleviation of symptoms. 8 This data also suggest that use of cannabis for symptom relief is common, and countries with legal access were found to have greater use of cannabis for managing endometriosis-related symptoms than those without legal access. 9 Additional self-reported survey data shows cannabis was efficacious in reducing pelvic pain, improving sleep, and reducing anxiety and depression, as well as managing symptoms of nausea and vomiting that can be associated with endometriosis.8–11 Data also showed an inclination for women to favor inhaled delivery of cannabis due to the rapid onset of effects and symptom alleviation compared with oral products. 12
Overall, results showed that cannabis consumption for symptom relief was common among women with endometriosis, and some women even reported that use of cannabis reduced their use of analgesics. All retrieved articles noted the need for future studies investigating cannabis use for pelvic pain, as well as the lack of clinical human studies to confirm what we know from animal studies.
Discussion
Endometriosis pain management is multifaceted and unique to each individual. The current evidence suggests potential therapeutic benefits of medical cannabis for endometriosis related pain. Most of the available data comes from self-reported cross-sectional surveys that have consistently shown that cannabis use is associated with the relief of endometriosis-associated symptoms compared with traditional therapies such as analgesics and heating pads. 13 Our analysis identified a clear lack of randomized controlled trials on the use of cannabis for endometriosis-related pain, indicating an important direction for future research given the recent findings that dysfunction in the endocannabinoid system (ECS) may play a role in endometriosis-related pain. 14
Marijuana, including cannabinoids such as THC and CBD that impact the endocannabinoid system, have the potential to effectively alleviate pain in several gynecological conditions, including chronic pelvic pain and endometriosis.15,16 Cannabinoid receptors are a part of a signaling system involved in many physiological processes, including pain sensation, appetite, and immune function. Expression of cannabinoid receptors (CB1 and CB2) has been shown in the endometrial glands of women with endometriosis, whereas no expression is seen in women with normal ovarian tissue. 14 Endometriotic lesions found in the ovaries are driven by the cyclic hormonal changes of the body and are the most common source of pain during the menstrual cycle. 17 Preclinical studies using animal models have shown promising results regarding antiproliferative effects of cannabinoids on endometriotic lesions, inhibiting the growth and spread of endometrial tissue outside the uterus in animal studies. 18
Inflammation plays a significant role in the development and progression of endometriosis. Several studies have investigated the anti-inflammatory effects of cannabis and its potential impact on endometriosis-associated inflammation. Cannabinoids have been shown to possess immunomodulatory properties and can reduce the release of inflammatory mediators.14,19 Preclinical studies have demonstrated that cannabinoids can attenuate inflammatory responses in endometriosis models.14,18–21 These findings suggest that cannabis may have potential anti-inflammatory effects that could be beneficial in managing endometriosis-related inflammation and associated pain.
Muscle cramps are a common symptom experienced by women with endometriosis, often causing severe, debilitating pain. Cannabinoids have antispasmodic effects, which can help relieve muscle tension and spasms identifying the potential for cannabis to reduce pain associated with endometriosis-related cramps (Fig. 1).
Therapeutic Targets of Cannabis for Relieving Endometriosis-Related Pain. This flow diagram illustrates the key therapeutic targets within the endocannabinoid system that interact with cannabis compounds. The interaction depicted above provide insights into the potential pathways for the applications of cannabis in the management of endometriosis-related pain.
Management of endometriosis typically includes a combination of medical and surgical interventions. Specific management is subject to variation based on severity of symptoms and desire for fertility, as well as individual patient preferences and history. For severe cases, surgery is often recommended. As no surgery comes without risks, the main goal of management of endometriosis is to alleviate symptoms and prevent the growth of further inappropriately located endometrial tissue. Emerging evidence suggests the endocannabinoid system, which regulates various physiological processes including pain perception and inflammation, may play a role in the pathophysiology of endometriosis. The ECS consists of cannabinoid receptors (CB1 and CB2) and endogenous cannabinoids (endocannabinoids) that bind to these receptors. 18 By targeting the ECS, cannabis may modulate pain signaling pathways and reduce pain intensity. 22 Research suggests that cannabis may act a potential analgesic agent, providing relief to individuals with chronic pain, including those with endometriosis (Fig. 1).23–24
The cannabinoid receptor 1 (CB1) is found in the amygdala, hippocampus, and cerebral cortex, areas that are highly associated with anxiety. 25 Anxiety is understood to be a complex biological process that can result from inappropriate activation of these receptors and circuits in the brain. As the endocannabinoid system plays a large role in modulation of these circuits, cannabinoids can have a biphasic effect on anxiety. As survey data suggest that women with endometriosis and/or polycystic ovarian syndrome commonly suffer from depression and/or anxiety in addition to their gynecological diagnoses, understanding the relationship between cannabis use, varying doses, and anxiety is an important component for clinicians to understand before considering cannabis for management of endometriosis-related pain.11,25
The safety and side effects of cannabis use are important considerations for management of endometriosis pain. The safety profile of cannabis has been investigated by several studies, which have indicated relatively mild and manageable side effects, such as dizziness, dry mouth, and fatigue. However, it is essential to consider potential interactions with other medications and individual variations in response by each patient. Further research is needed to thoroughly evaluate the safety and long-term effects of cannabis use specifically in women with endometriosis. Despite how common endometriosis is, it’s hypothesized that the number of women with endometriosis is underreported as many women go undiagnosed for years owing to lack of education on endometriosis, diagnostic challenges, misdiagnosis due to overlap with other conditions, and gender biases.
Conclusion
The current literature provides valuable insights into the potential use of cannabis for managing endometriosis-related pain. However, there are still gaps and limitations that remain necessary to address to enhance our understanding of the therapeutic potential and risks associated with cannabis use in women with endometriosis. Existing studies are limited by small sample sizes, variations in study design, and the predominance of preclinical and observational studies. Our findings emphasize the necessity of well-designed, blinded, randomized trials to ascertain the safety and efficacy of different cannabis dosages and administration methods that are legally available to determine the short- and long-term benefits and risks of using medical cannabis in the management of endometriosis.
Footnotes
Author’s Contributions
All authors made substantive contributions to the development, design, and writing of this article. S.C., led the development of the concept, registered the review protocol, analyzed the data, and led the article writing. K.K. contributed to data analysis, development of the background literature review, and article writing. N.E. led the development and conceptualization of the study design and data analysis plan, contributed to the interpretation of the findings and writing of the article. R.R. conducted the initial literature search and authored the methods section of the article.
Author Disclosure Statement
Savannah Calleson Cummings, MS, Nicole Ennis, PhD and Katie Kloss, BA have no conflict of interest to report.
Funding Information
This work was supported by pilot funding awarded to Dr. Nicole Ennis from