The endocannabinoid system consists of lipid signaling molecules called endocannabinoids, principally anandamide and 2-arachidonoylglycerol, along with their G-protein-coupled receptors, CB1 and CB2, and the enzymes that synthesize and degrade these messengers. CB1 receptors are abundant on nociceptive sensory neurons in the dorsal root ganglia, where their activation dampens the release of pain-transmitting neurotransmitters. CB2 receptors are found predominantly on immune cells, including mast cells and macrophages, and their engagement suppresses the release of proinflammatory cytokines. Beyond these classic receptors, cannabinoids also interact with non-cannabinoid targets such as the ion channel TRPV1, the nuclear receptor PPAR-gamma, serotonin receptors, and orphan G-protein-coupled receptors like GPR18 and GPR55, giving the system an unusually broad pharmacological reach.

What makes this system particularly relevant to endometriosis is that it is not merely a bystander. Human studies have documented elevated systemic levels of endocannabinoids and related mediators across the menstrual cycle in women with endometriosis, and cannabinoid receptor expression has been detected directly in endometriotic lesions. Animal work has shown that the CB1 receptor contributes to the development of ectopic lesions in a mouse model of the disease, while other studies report decreased expression of cannabinoid receptors in the eutopic and ectopic endometrium of patients with adenomyosis, a closely related condition. In other words, the endocannabinoid machinery appears to be rewired in diseased tissue, positioning it as both a marker and a potential driver of pathology.

The review organizes the therapeutic logic of cannabinoids around three mechanistic pillars: inflammation, nociceptive signaling, and lesion proliferation. On the inflammatory front, endometriosis is characterized by a peritoneal environment awash with proinflammatory cytokines, activated macrophages, and degranulating mast cells, all of which sensitize nearby nerve fibers. Cannabinoids attenuate this cascade by inhibiting proinflammatory cytokine signaling and reducing the release of inflammatory mediators from mast cells and peritoneal macrophages. Cannabidiol, the non-psychoactive phytocannabinoid, has been shown in molecular studies to blunt the inflammatory and oxidative processes associated with endometriosis, and CB2-selective agonists reduce cytokine release in blood mononuclear cells. Because neurogenic inflammation, driven by mast cells and nerve fiber interactions, is increasingly recognized as central to endometriosis pain, this immunomodulatory action is a plausible route to symptom control.

The second pillar concerns direct suppression of pain signaling and sensitization. Endometriosis-associated pain involves peripheral, central, and cross-sensitization, in which repeated nociceptive input from pelvic lesions amplifies responses throughout the nervous system, sometimes producing comorbid pain syndromes such as fibromyalgia. Cannabinoids counter this at multiple levels. Activation of peripheral CB1 and CB2 receptors suppresses the maintenance of inflammatory nociception, and genetic studies indicate that cannabinoid analgesia is mediated largely through peripheral type 1 cannabinoid receptors on nociceptors. Cannabidiol acts on TRPV1 signaling pathways in cultured dorsal root ganglion neurons, and CB1 receptor agonists can prevent nerve growth factor-induced sensitization of TRPV1 in sensory neurons, a mechanism directly relevant to the elevated TRPV1 expression observed in the dorsal root ganglia of rats with endometriosis and in peritoneal endometriotic foci of women with chronic pelvic pain.

The third pillar is antiproliferative. Endometriotic lesions behave somewhat like benign tumors, proliferating, invading, and recruiting new blood vessels. Synthetic cannabinoid agonists such as WIN 55212-2 have been shown to target proliferation, angiogenesis, and apoptosis via MAPK/AKT signaling in human endometriotic cell lines and in a murine model of the disease. Cannabinoid agonists exert antiproliferative effects on deep infiltrating endometriosis tissue, and cannabidiol demonstrated anti-inflammatory, antioxidative, and antiangiogenic effects in an experimental rat model. Natural delta-9-tetrahydrocannabinol has even shown disease-modifying effects on endometriosis-associated pain in animal studies, suggesting that cannabinoids might not only mask symptoms but also slow lesion growth, a property that no current medical therapy can claim.

The mechanistic enthusiasm is mirrored by striking epidemiological reality. Surveys from Australia, New Zealand, Canada, Germany, and the United States consistently show that large numbers of women with endometriosis are already using cannabis, often illicitly or without medical supervision, to self-manage their pain, and many report perceived effectiveness. A national survey of Australian women identified cannabis as a common self-management strategy, and international cross-sectional research conducted during the COVID-19 pandemic documented continued and in some cases increased use. National survey data further indicate substantial willingness among women to try cannabis for gynecological conditions. This grassroots adoption has outpaced the clinical evidence, creating a situation in which patients are experimenting on themselves with products of variable composition and dosing, while physicians lack the trial data needed to guide them.

The review’s authors argue that this gap makes properly controlled clinical trials an urgent priority. Several challenges stand in the way. Cannabinoid pharmacology is complicated by the entourage effect, in which combinations of phytocannabinoids and terpenes may produce effects different from isolated compounds, and by the psychoactivity of THC, which limits tolerable doses. However, recent structural and pharmacological advances are opening new doors. The discovery of a cryptic pocket in the CB1 receptor that drives peripheral and functional selectivity suggests it may be possible to design analgesics that activate pain-relieving pathways without central psychoactive effects. Separately, the sodium channel Nav1.8 has been identified as an analgesic target for non-psychotomimetic phytocannabinoids, offering another route to pain relief without intoxication. Such advances could yield peripherally restricted cannabinoid medicines tailored to endometriosis, an approach that would sidestep many of the regulatory and tolerability obstacles that have hampered the field.

There is also an opioid angle that gives the research public-health urgency. Women with endometriosis are frequently prescribed opioids for their pain, and cohort studies in US administrative claims data have documented chronic opioid use and its complication risks in this population. Cannabinoids interact with the opioid system, and a growing body of preclinical and clinical evidence supports an opioid-sparing effect of cannabinoids for analgesia. Because cannabinoid receptor expression has been detected in endometriotic lesions of women with the disease, some researchers have proposed cannabinoid-based approaches as an alternative to opioid-based pain medication. If clinical trials confirm meaningful analgesia, cannabinoids could help reduce opioid exposure in a patient population disproportionately affected by long-term opioid therapy and its attendant risks of dependence and hyperalgesia.

Cautious optimism is the appropriate stance. The evidence base remains dominated by in vitro studies and animal models, and human interventional data are still sparse, while the endocannabinoid system also plays fundamental roles in endometrial and placental biology, raising questions about reproductive safety that trials must address. Yet the convergence of epidemiological demand, mechanistic plausibility across inflammation, nociception, and proliferation, and emerging medicinal chemistry that promises non-psychoactive, peripherally targeted drugs makes the endocannabinoid system one of the most compelling therapeutic frontiers in endometriosis research. As the Wayne State team concludes, the system’s regulation of nociception, inflammation, and lesion growth warrants rigorous clinical evaluation, and for the millions of women whose pain has outlasted every existing therapy, that evaluation cannot come soon enough.

Subject of Research: The role of the endocannabinoid system in the mechanisms and treatment of endometriosis-associated pain

Article Title: The Endocannabinoid System in Endometriosis-Associated Pain: Mechanisms, Molecular Targets, and Therapeutic Implications

Article References: Stone, A. M., Veltre, V. L., Camp, O. G., Biernat, M. M., & Abu-Soud, H. M. (2026). The Endocannabinoid System in Endometriosis-Associated Pain: Mechanisms, Molecular Targets, and Therapeutic Implications. Reproductive Sciences. https://doi.org/10.1007/s43032-026-02201-9

Image Credits: AI Generated

DOI: 10.1007/s43032-026-02201-9

Keywords: endometriosis, endocannabinoid system, cannabinoids, cannabidiol, chronic pelvic pain, CB1 receptor, CB2 receptor, inflammation, nociception, TRPV1, lesion proliferation, clinical trials