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

Posted on September 26, 2026 by David Worrell

A new 2026 review published in Reproductive Sciences examines the endocannabinoid system (ECS) as a therapeutic target for endometriosis-associated pain, a condition that can cause severe pelvic pain, painful menstruation, painful intercourse, and other chronic symptoms. The authors highlight the ECS because of its established roles in regulating pain, inflammation, and immune activity.

The review found that cannabinoids may influence three major mechanisms involved in endometriosis-associated pain: inflammation, pain signaling and sensitization, and the growth of endometriotic lesions. Cannabinoids interact with both cannabinoid and non-cannabinoid receptors found in endometriotic tissue, while also reducing inflammatory signaling from immune cells such as mast cells and macrophages.

The researchers conclude that the endocannabinoid system is a promising therapeutic target for endometriosis-associated pain, with cannabinoid therapies showing potential to regulate nociception, inflammation, and lesion proliferation. They call for clinical trials to further evaluate cannabinoid-based treatments for people living with endometriosis.

“Endometriosis is a chronic gynecological disorder affecting approximately 10% of reproductive-age women, characterized by the ectopic growth of endometrial tissue and severe pain, including dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, and dyschezia. Current treatments are limited in efficacy and associated with significant side effects, underscoring the urgent need for novel therapeutic strategies.

The endocannabinoid system (ECS) has emerged as a promising therapeutic target, given its well-established roles in pain modulation, inflammation, and immune regulation. Epidemiological evidence demonstrates that women with endometriosis increasingly use cannabis for symptom self-management, yet the underlying mechanisms remain poorly characterized.

This review integrates preclinical and human evidence to comprehensively evaluate the mechanistic basis of cannabinoid efficacy in endometriosis-associated pain. Evidence from in vitro studies and animal models indicates that cannabinoids target three main mechanisms of endometriosis-associated pain, including inflammation, nociceptive signaling, and lesion proliferation.

Cannabinoids suppress pain signaling and sensitization by interacting with cannabinoid and non-cannabinoid receptors expressed in endometriotic lesions. Cannabinoids attenuate endometriosis-induced inflammation by inhibiting proinflammatory cytokine signaling and reducing the release of inflammatory mediators by mast cells and peritoneal macrophages. Cannabinoids also exert antiproliferative effects in endometriosis models, thereby suppressing the growth of endometriotic lesions.

In conclusion, the ECS is a promising therapeutic target for endometriosis-associated pain, as it regulates nociception, inflammation, and proliferation. These promising findings highlight the potential therapeutic benefits of cannabinoids for endometriosis-associated pain, warranting the need for clinical trials to evaluate the safety and effectiveness of cannabinoid therapies in endometriosis.”

https://pubmed.ncbi.nlm.nih.gov/42745018

https://link.springer.com/article/10.1007/s43032-026-02201-9

Combined Cannabidiol and Δ9-Tetrahydrocannabinol Modulate Inflammation and Nociceptive Signaling in Human Dental Pulp Cells

Posted on September 14, 2026 by David Worrell

A new study using human dental pulp cells found that combining cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) produced stronger anti-inflammatory effects than either cannabinoid alone. The combination reduced the pro-inflammatory cytokines IL-6, IL-12, and IL-1β while increasing the anti-inflammatory cytokine IL-10.

CBD and THC together also influenced important pathways involved in pain signaling and healing. Researchers reported increased expression of the cannabinoid receptors CNR1 and CNR2, modulation of TRPV1, and enhanced cell proliferation and migration. The combination also promoted mineralized nodule formation and increased markers associated with odontogenic differentiation and new blood-vessel formation.

The researchers concluded that combined CBD and THC show promise for promoting dental pulp healing by simultaneously influencing inflammation, nociceptive signaling, tissue repair, angiogenesis, and cell migration. The findings provide new evidence that cannabinoids may have potential applications in future vital pulp therapies designed to preserve and regenerate living dental tissue.

“Introduction: Dental pulp inflammation, caused by caries, trauma, or restorative operations, produces pain and slows regeneration. Cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), cannabinoids of Cannabis sativa, have effects on inflammation and pain relief. However, the impact of these factors on dental pulp healing is not understood. This study investigated the combined effects of CBD and THC in controlling inflammation and nociception during dental pulp repair.

Methods: Human dental pulp cells were stimulated with lipopolysaccharide (LPS) and treated with CBD (2.5 μg/mL), THC (0.6 μg/mL), and their combination. Pro-inflammatory cytokines (IL-6, IL-12 and IL-1β) and anti-inflammatory cytokine IL-10 were analysed using qPCR and ELISA, while anti-nociceptive markers (CNR1, CNR2, and TRPV1) were evaluated by qPCR and Western blot. Cell viability, proliferation, and migration assays were performed to evaluate treatment effects on cellular behaviours associated with pulpal repair and regenerative potential.

Results: Compared with either treatment alone, the CBD/THC combination more effectively attenuated pro-inflammatory cytokines IL-6, IL-12, and IL-1β, enhanced CNR1 and CNR2 expression, modulated TRPV1, and increased IL-10 expression. Viability assays determined optimal non-cytotoxic concentrations for treatment. The combination enhanced cell proliferation and migration, promoted mineralized nodule formation, and significantly upregulated markers associated with tissue repair, odontogenic differentiation (DMP1), and angiogenesis (VEGF and bFGF).

Conclusion: Combined CBD and THC show promise for promoting dental pulp healing by modulating inflammation and nociceptive signaling, while supporting odontogenic differentiation, angiogenesis, and cell migration in human dental pulp cells. These findings provide in vitro evidence supporting combined cannabinoid treatment as a therapeutic strategy for vital pulp therapies.”

https://pubmed.ncbi.nlm.nih.gov/42722230

https://www.jendodon.com/article/S0099-2399(26)00500-5/abstract

Endocannabinoids and endocannabinoid-like compounds modulate hypoxia-induced permeability in CaCo-2 cells via CB1, TRPV1, and PPARα.

Posted on July 22, 2019 by David Worrell

Biochemical Pharmacology “We have previously reported that endocannabinoids modulate permeability in Caco-2 cells under inflammatory conditions and hypothesised in the present study that endocannabinoids could also modulate permeability in ischemia/reperfusion.

CONCLUSIONS AND IMPLICATIONS:

A variety of endocannabinoids and endocannabinoid-like compounds modulate Caco-2 permeability in hypoxia/reoxygenation, which involves multiple targets, depending on whether the compounds are applied to the basolateral or apical membrane. CB₁ antagonism and TRPV1 or PPARα agonism may represent novel therapeutic targets against several intestinal disorders associated with increased permeability.”

https://www.ncbi.nlm.nih.gov/pubmed/31325449

https://www.sciencedirect.com/science/article/abs/pii/S0006295219302722?via%3Dihub

Antitumor Cannabinoid Chemotypes: Structural Insights.

Posted on June 20, 2019 by David Worrell

Image result for frontiers in pharmacology “Cannabis has long been known to limit or prevent nausea and vomiting, lack of appetite, and pain. For this reason, cannabinoids have been successfully used in the treatment of some of the unwanted side effects caused by cancer chemotherapy.

Besides their palliative effects, research from the past two decades has demonstrated their promising potential as antitumor agents in a wide variety of tumors.

Cannabinoids of endogenous, phytogenic, and synthetic nature have been shown to impact the proliferation of cancer through the modulation of different proteins involved in the endocannabinoid system such as the G protein-coupled receptors CB1, CB2, and GRP55, the ionotropic receptor TRPV1, or the fatty acid amide hydrolase (FAAH).

In this article, we aim to structurally classify the antitumor cannabinoid chemotypes described so far according to their targets and types of cancer. In a drug discovery approach, their in silico pharmacokinetic profile has been evaluated in order to identify appropriate drug-like profiles, which should be taken into account for further progress toward the clinic.

This analysis may provide structural insights into the selection of specific cannabinoid scaffolds for the development of antitumor drugs for the treatment of particular types of cancer.” https://www.ncbi.nlm.nih.gov/pubmed/31214034

“The first report on the antitumor activity of phytocannabinoids was published over four decades ago. During these last years, significant research has been focused on the therapeutic potential of cannabinoids to manage palliative effects in cancer patients. Besides such palliative applications, some cannabinoids have shown anticancer properties. Since inflammation is a common risk factor for cancer, and some cannabinoids have shown anti-inflammatory properties, they could play a role in chemoprevention.” https://www.frontiersin.org/articles/10.3389/fphar.2019.00621/full

“Antitumor effects of THC.” http://www.ncbi.nlm.nih.gov/pubmed/11097557
“Antitumor effects of cannabidiol” http://www.ncbi.nlm.nih.gov/pubmed/14617682
“Anti-tumour actions of cannabinoids.” https://www.ncbi.nlm.nih.gov/pubmed/30019449
“Extensive preclinical research has demonstrated that cannabinoids, the active ingredients of Cannabis sativa, trigger antitumor responses in different models of cancer.” https://www.ncbi.nlm.nih.gov/pubmed/29940172

New Insights of Uterine Leiomyoma Pathogenesis: Endocannabinoid System.

Posted on March 8, 2019 by David Worrell

“The aim of this study was to determine if components of the endocannabinoid system are modulated in uterine leiomyomas (fibroids). Components studied included cannabinoid receptors 1 (CB1) and 2 (CB2); the G protein-coupled receptor GPR55; transient potential vanilloid receptor 1 (TRPV1) and the endocannabinoid modulating enzymes N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), and their N-acylethanolamine (NAE) ligands: N-arachidonylethanolamine (AEA), N-oleoylethanolamine (OEA), and N-palmityolethanaolamine (PEA). MATERIAL AND METHODS Transcript levels of CB1, CB2, TRPV1, GPR55, NAPE-PLD, and FAAH were measured using RT-PCR and correlated with the tissue levels of the 3 NAEs in myometrial tissues. The tissues studied were: 1) fibroids, 2) myometrium adjacent/juxtaposed to the fibroid lesions, and 3) normal myometrium. Thirty-seven samples were processed for NAE measurements and 28 samples were used for RT-PCR analyses. RESULTS FAAH expression was significantly lower in fibroids, resulting in a NAPE-PLD: FAAH ratio that favors higher AEA levels in pre-menopausal tissues, whilst PEA levels were significantly lower, particularly in post-menopausal women, suggesting PEA protects against fibroid pathogenesis. The CB1: CB2 ratio was lower in fibroids, suggesting that loss of CB1 expression affects the fibroid cell phenotype. Significant correlations between reduced FAAH, CB1, and GPR55 expression and PEA in fibroids indicate that the loss of these endocannabinoid system components are biomarkers of leiomyomata. CONCLUSIONS Loss of expression of CB1, FAAH, GPR55, and PEA production are linked to the pathogenesis of uterine fibroids and further understanding of this might eventually lead to better disease indicators or the development of therapeutic potentials that might eventually be used in the management of uterine fibroids.”

https://www.ncbi.nlm.nih.gov/pubmed/30842391

https://basic.medscimonit.com/abstract/index/idArt/914019

Effects of CB2 and TRPV1 receptors’ stimulation in pediatric acute T-lymphoblastic leukemia

Posted on May 17, 2018 by David Worrell

“T-Acute Lymphoblastic Leukemia (T-ALL) is less frequent than B-ALL, but it has poorer outcome. For this reason new therapeutic approaches are needed to treat this malignancy.

The Endocannabinoid/Endovanilloid (EC/EV) system has been proposed as possible target to treat several malignancies, including lymphoblastic diseases. The EC/EV system is composed of two G-Protein Coupled Receptors (CB1 and CB2), the Transient Potential Vanilloid 1 (TRPV1) channel, their endogenous and exogenous ligands and enzymes. CB1 is expressed mainly in central nervous system while CB2 predominantly on immune and peripheral cells, therefore we chose to selectively stimulate CB2 and TRPV1.

We treated T-ALL lymphoblasts derived from 4 patients and Jurkat cells with a selective agonist at CB2 receptor: JWH-133 [100 nM] and an agonist at TRPV1 calcium channel: RTX [5 uM] at 6, 12 and 24 hours. We analyzed the effect on apoptosis and Cell Cycle Progression by a cytofluorimetric assays and evaluated the expression level of several target genes (Caspase 3, Bax, Bcl-2, AKT, ERK, PTEN, Notch-1, CDK2, p53) involved in cell survival and apoptosis, by Real-Time PCR and Western Blotting.

We observed a pro-apoptotic, anti-proliferative effect of these compounds in both primary lymphoblasts obtained from patients with T-ALL and in Jurkat cell line. Our results show that both CB2 stimulation and TRPV1 activation, can increase the apoptosis in vitro, interfere with cell cycle progression and reduce cell proliferation, indicating that a new therapeutic approach to T-cell ALL might be possible by modulating CB2 and TRPV1 receptors.”

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=25052

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Marijuana compounds show promise in treatment of cardiac disease

Posted on April 27, 2017 by David Worrell

“A Nevada company is hoping to develop new medicines for heart failure using compounds in marijuana and a novel therapy identified by a University of Hawaiʻi at Mānoa researcher. Dr. Alexander Stokes, assistant research professor in the Department of Cell and Molecular Biology at the UH John A. Burns School of Medicine, obtained a U.S. patent for his novel therapy in 2015. The patent claims the cannabinoid receptor TRPV1 can be regulated therapeutically by plant-based cannabinoids.” https://medicalxpress.com/news/2017-01-marijuana-compounds-treatment-cardiac-disease.html

“Marijuana compounds show promise in treatment of cardiac disease” http://manoa.hawaii.edu/news/article.php?aId=8355

“Marijuana compounds show promise in treatment of cardiac disease” http://www.hawaii.edu/news/2017/01/12/marijuana-compounds-show-promise-in-treatment-of-cardiac-disease/

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The endocannabinoid system as a target for novel anxiolytic drugs.

Posted on April 25, 2017 by David Worrell

“The endocannabinoid (eCB) system has attracted attention for its role in various behavioral and brain functions, and as a therapeutic target in neuropsychiatric disease states, including anxiety disorders and other conditions resulting from dysfunctional responses to stress. In this mini-review, we highlight components of the eCB system that offer potential ‘druggable’ targets for new anxiolytic medications, emphasizing some of the less well-discussed options. We discuss how selectively amplifying eCBs recruitment by interfering with eCB-degradation, via fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been linked to reductions in anxiety-like behaviors in rodents and variation in human anxiety symptoms. We also discuss a non-canonical route to regulate eCB degradation that involves interfering with cyclooxygenase-2 (COX-2). Next, we discuss approaches to targeting eCB receptor-signaling in ways that do not involve the cannabinoid receptor subtype 1 (CB1R); by targeting the CB2R subtype and the transient receptor potential vanilloid type 1 (TRPV1). Finally, we review evidence that cannabidiol (CBD), while representing a less specific pharmacological approach, may be another way to modulate eCBs and interacting neurotransmitter systems to alleviate anxiety. Taken together, these various approaches provide a range of plausible paths to developing novel compounds that could prove useful for treating trauma-related and anxiety disorders.” https://www.ncbi.nlm.nih.gov/pubmed/28434588]]>

Dual-Acting Compounds Targeting Endocannabinoid and Endovanilloid Systems-A Novel Treatment Option for Chronic Pain Management.

Posted on September 3, 2016 by David Worrell

“Compared with acute pain that arises suddenly in response to a specific injury and is usually treatable, chronic pain persists over time, and is often resistant to medical treatment.

Because of the heterogeneity of chronic pain origins, satisfactory therapies for its treatment are lacking, leading to an urgent need for the development of new treatments.

The leading approach in drug design is selective compounds, though they are often less effective and require chronic dosing with many side effects.

Herein, we review novel approaches to drug design for the treatment of chronic pain represented by dual-acting compounds, which operate at more than one biological target.

A number of studies suggest the involvement of the cannabinoid and vanilloid receptors in pain.

Interestingly cannabinoid system is in interrelation with other systems that comprise lipid mediators: prostaglandins, produced by COX enzyme.

Therefore, in the present review, we summarize the role of dual-acting molecules (FAAH/TRPV1 and FAAH/COX-2 inhibitors) that interact with endocannabinoid and endovanillinoid systems and act as analgesics by elevating the endogenously produced endocannabinoids and dampening the production of pro-inflammatory prostaglandins.

The plasticity of the endocannabinoid system (ECS) and the ability of a single chemical entity to exert an activity on two receptor systems has been developed and extensively investigated.

Here, we review up-to-date pharmacological studies on compounds interacting with FAAH enzyme together with TRPV1 receptor or COX-2 enzyme respectively.

Multi-target pharmacological intervention for treating pain may lead to the development of original and efficient treatments.”

http://www.ncbi.nlm.nih.gov/pubmed/27582708

Metabolism of endocannabinoids.

Posted on August 16, 2016 by David Worrell

“Endocannabinoids belong to a group of ester, ether and amide derivatives of fatty acids, which are endogenous ligands of receptors CB1, CB2, TRPV1 and GPR55 that are included in the endocannabinoid system of the animal organism. The best known endocannabinoids are: N-arachidonylethanolamide called anandamide (AEA) and 2-arachidonoylglycerol (2-AG). They occur in all organisms, and their highest level is observed in the brain. In this review the mechanisms of synthesis and degradation of both AEA and 2-AG are shown. Endocannabinoids are synthesized from phospholipids (mainly phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol) located in the cell membrane. As a result of arachidonic acid transfer from phosphatidylcholine to phosphatidylethanolamine, N-arachidonoyl phosphatidylethanolamine is formed, which is hydrolyzed to AEA by phospholipase D, C and A2. However, 2-AG is formed during the hydrolysis of phosphatidylinositol catalyzed mainly by DAGL. The primary role of endocannabinoids is the activation of cannabinoid receptors. Both AEA and 2-AG are primarily agonists of the CB1 receptor and to a lower degree CB2 and TRPV1r eceptors, but 2-AG has stronger affinity for these receptors. Through activation of receptors, endocannabinoids affect cellular metabolism and participate in the metabolic processes by receptor-independent pathways. Endocannabinoids which are not bound to the receptors are degraded. The main enzymes responsible for the hydrolysis of AEA and 2-AG are FAAH and MAGL, respectively. Apart from hydrolytic degradation, endocannabinoids may also be oxidized by cyclooxygenase-2, lipoxygenases, and cytochrome P450. It has been shown that the metabolites of both endocannabinoids also have biological significance.”

http://www.ncbi.nlm.nih.gov/pubmed/27516570

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