Abstract
Research question
Can cannabidiol (CBD) be used in the treatment of endometriosis for its anti-inflammatory,
antioxidative and antiangiogenic effects?
Design
Endometrial implants were surgically induced in 36 female Wistar albino rats. After
confirmation of endometriotic foci, the rats were randomized into four groups. In
the leuprolide acetate group, rats were given a single 1 mg/kg s.c. leuprolide acetate
injection. The other groups were 5 mg/kg CBD (CBD5), saline solution and 20 mg/kg
CBD (CBD20); daily i.p. injections were administered for 7 days. After 21 days, the
rats were euthanised, and total antioxidant status (TAS), total oxidant status (TOS),
oxidative stress index (OSI), interleukin-6 (IL-6) and tumour necrosis factor-alpha
(TNF-α) measurements in blood and peritoneal fluid samples, and immunohistochemical
staining for TNF-α, IL-6 and vascular endothelial growth factor (VEGF) of endometriotic
tissues were evaluated.
Results
Significant reductions in the endometriotic implant surface area (P = 0.0213), serum TOS (P = 0.0491), OSI (P = 0.0056), IL-6 (P = 0.0236), TNF-α (P = 0.0083) and peritoneal fluid OSI (P = 0.0401), IL-6 (P = 0.0205) and TNF-α (P = 0.0045) concentrations were observed in the CBD5 group when compared with the saline
solution group. Compared with the saline solution group, increased TAS concentrations
in serum (P = 0.0012) and peritoneal fluid (P = 0.0145) were found in the CBD5 group. The CBD5 and leuprolide acetate groups were
similar regarding inflammatory and oxidative stress parameters of serum and peritoneal
fluid samples. The CBD5 group showed significantly lower mean intensity in both surface
epithelium and stromal cells for VEGF (both P = 0.002) and only in surface epithelium cells for IL-6 (P = 0.0108), when compared with the leuprolide acetate group.
Conclusion
Due to its anti-inflammatory, antioxidative and antiangiogenic effects, CBD might
be a therapeutic agent candidate for endometriosis.
Keywords
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References
- Self-management strategies amongst Australian women with endometriosis: a national online survey.BMC Complement. Altern. Med. 2019; 19: 17https://doi.org/10.1186/s12906-019-2431-x
- Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer.J. Mol. Med. (Berl). 2012; 90: 925-934https://doi.org/10.1007/s00109-011-0856-x
- Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial.Hum. Reprod. 2002; 17: 426-431https://doi.org/10.1093/humrep/17.2.426
- Endocannabinoids modulate apoptosis in endometriosis and adenomyosis.Acta Histochem. 2017; 119: 523-532https://doi.org/10.1016/j.acthis.2017.05.005
- Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis.J. Mol. Med. (Berl). 2009; 87: 1111-1121https://doi.org/10.1007/s00109-009-0512-x
- Peritoneal fluid-mediated enhancement of eutopic and ectopic endometrial cell proliferation is dependent on tumor necrosis factor-alpha in women with endometriosis.Fertil. Steril. 2002; 78: 727-732https://doi.org/10.1016/s0015-0282(02)03318-6
- Pathogenesis and pathophysiology of endometriosis.Fertil. Steril. 2012; 98: 511-519https://doi.org/10.1016/j.fertnstert.2012.06.029
- Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications.Drug Alcohol Depend. 2014; 144: 12-41https://doi.org/10.1016/j.drugalcdep.2014.08.005
- From pathogenesis to clinical practice: emerging medical treatments for endometriosis.Best Pract. Res. Clin. Obstet. Gynaecol. 2018; 51: 92-101https://doi.org/10.1016/j.bpobgyn.2018.01.021
- Eutopic and ectopic stromal cells from patients with endometriosis exhibit differential invasive, adhesive, and proliferative behavior.Fertil. Steril. 2013; 100: 761-769https://doi.org/10.1016/j.fertnstert.2013.04.041
- The endocannabinoid pathway and the female reproductive organs.J. Mol. Endocrinol. 2013; 50: R1-R9https://doi.org/10.1530/JME-12-0182
- Endocannabinoid involvement in endometriosis.Pain. 2010; 151: 703-710https://doi.org/10.1016/j.pain.2010.08.037
- Vascular endothelial growth factor (VEGF) in endometriosis.Hum. Reprod. 1998; 13: 1686-1690https://doi.org/10.1093/humrep/13.6.1686
- Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury.Am. J. Physiol. Heart Circ. Physiol. 2007; 293: H3602-H3607https://doi.org/10.1152/ajpheart.00098.2007
- Tumor necrosis factor in peritoneal fluid of women undergoing laparoscopic surgery.Fertil. Steril. 1988; 50: 573-579https://doi.org/10.1016/s0015-0282(16)60185-1
- Disease-modifying effects of natural Δ9-tetrahydrocannabinol in endometriosis-associated pain.eLife. 2020; 9: e50356https://doi.org/10.7554/eLife.50356
- Tumor angiogenesis: therapeutic implications.N. Engl. J. Med. 1971; 285: 1182-1186https://doi.org/10.1056/NEJM197111182852108
- Antitumorigenic effects of cannabinoids beyond apoptosis.J. Pharmacol. Exp. Ther. 2010; 332: 336-344https://doi.org/10.1124/jpet.109.157735
- Comparison of HSCORE assessment of endometrial beta3 integrin subunit expression with digital HSCORE using computerized image analysis (ImageJ).Anal. Quant. Cytopathol. Histopathol. 2013; 35: 210-216
- Autocrine and paracrine regulation of lymphocyte CB2 receptor expression by TGF-beta.Biochem. Biophys. Res. Commun. 2002; 290: 91-96https://doi.org/10.1006/bbrc.2001.6179
- Endocannabinoid system regulates migration of endometrial stromal cells via cannabinoid receptor 1 through the activation of PI3K and ERK1/2 pathways.Fertil. Steril. 2010; 93: 2588-2593https://doi.org/10.1016/j.fertnstert.2010.02.006
- Role of oxidative stress in endometriosis.Reprod. Biomed. Online. 2006; 13: 126-134https://doi.org/10.1016/S1472-6483(10)62026-3
- Cannabinoid receptor 1 contributes to sprouted innervation in endometrial ectopic growth through mitogen-activated protein kinase activation.Brain Res. 2017; 1663: 132-140https://doi.org/10.1016/j.brainres.2017.03.016
- Increased interleukin-6 levels in peritoneal fluid of infertile patients with active endometriosis.Am. J. Obstet. Gynecol. 1997; 176: 593-597https://doi.org/10.1016/s0002-9378(97)70553-2
- Cannabinoid physiology and pharmacology: 30 years of progress.Neuropharmacology. 2004; 47: 345-358https://doi.org/10.1016/j.neuropharm.2004.07.030
- Rimonabant inhibits TNF-α-induced endothelial IL-6 secretion via CB1 receptor and cAMP-dependent protein kinase pathway.Acta Pharmacol. Sin. 2010; 31: 1447-1453https://doi.org/10.1038/aps.2010.126
- An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies.Cannabis Cannabinoid Res. 2017; 2: 139-154https://doi.org/10.1089/can.2016.0034
- Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb.Trends Pharmacol. Sci. 2009; 30: 515-527https://doi.org/10.1016/j.tips.2009.07.006
- World Endometriosis Society consensus on the classification of endometriosis.Hum. Reprod. 2017; 32: 315-324https://doi.org/10.1093/humrep/dew293
- Cannabidiol – from plant to human body: a promising bioactive molecule with multi-target effects in cancer.Int. J. Mol. Sci. 2019; 20https://doi.org/10.3390/ijms20235905
- A cannabinoid quinone inhibits angiogenesis by targeting vascular endothelial cells.Mol. Pharmacol. 2006; 70: 51-59https://doi.org/10.1124/mol.105.021089
- Antiproliferative effects of cannabinoid agonists on deep infiltrating endometriosis.Am. J. Pathol. 2010; 177: 2963-2970https://doi.org/10.2353/ajpath.2010.100375
- Differential expression of cannabinoid CB(2) receptor mRNA in mouse immune cell subpopulations and following B cell stimulation.Eur. J. Pharmacol. 2001; 423: 235-241https://doi.org/10.1016/s0014-2999(01)01122-0
- Neutrophils and macrophages promote angiogenesis in the early stage of endometriosis in a mouse model.Endocrinology. 2006; 147: 1278-1286https://doi.org/10.1210/en.2005-0790
- Cannabinoids in gynecological diseases.Med. Cannabis Cannabinoids. 2019; 2: 14-21https://doi.org/10.1159/000499164
- Higher expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) and metalloproteinase-9 (MMP-9) in a rat model of peritoneal endometriosis is similar to cancer diseases.J. Exp. Clin. Cancer Res. 2010; 29: 4https://doi.org/10.1186/1756-9966-29-4
- Endometriosis and angiogenesis.Minerva Ginecol. 2008; 60: 245-254
- Vascular endothelial growth factor and endometriotic angiogenesis.Hum. Reprod. Update. 2000; 6: 45-55https://doi.org/10.1093/humupd/6.1.45
- Are cannabidiol and Δ(9)-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review.Br. J. Pharmacol. 2015; 172: 737-753https://doi.org/10.1111/bph.12944
- A systematic review of cannabidiol dosing in clinical populations.Br. J. Clin. Pharmacol. 2019; 85: 1888-1900https://doi.org/10.1111/bcp.14038
- The highs and lows of cannabinoid receptor expression in disease: mechanisms and their therapeutic implications.Pharmacol. Rev. 2011; 63: 461-470https://doi.org/10.1124/pr.110.003491
- The effect of captopril on endometriotic implants in a rat model.Eur. J. Obstet. Gynecol. Reprod. Biol. 2014; 180: 120-125https://doi.org/10.1016/j.ejogrb.2014.06.028
- Endocannabinoids and cannabinoid receptor genetics.Prog. Neurobiol. 2002; 66: 307-344https://doi.org/10.1016/s0301-0082(02)00007-2
- A potential novel treatment strategy: inhibition of angiogenesis and inflammation by resveratrol for regression of endometriosis in an experimental rat model.Gynecol. Endocrinol. Off. J. Int. Soc. Gynecol. Endocrinol. 2015; 31: 219-224https://doi.org/10.3109/09513590.2014.976197
- Presence and functional regulation of cannabinoid receptors in immune cells.Life Sci. 1999; 65: 637-644https://doi.org/10.1016/s0024-3205(99)00286-6
- Pharmacology of cannabinoid CB1 and CB2 receptors.Pharmacol. Ther. 1997; 74: 129-180https://doi.org/10.1016/s0163-7258(97)82001-3
- The cannabinoid delta-9-tetrahydrocannabinol mediates inhibition of macrophage chemotaxis to RANTES/CCL5: linkage to the CB2 receptor.J. Neuroimmune Pharmacol. 2008; 3: 117-129https://doi.org/10.1007/s11481-007-9077-z
- The rat as an animal model for endometriosis to examine recurrence of ectopic endometrial tissue after regression.Fertil. Steril. 1990; 53: 921-925https://doi.org/10.1016/s0015-0282(16)53532-8
- Self-reported efficacy of cannabis for endometriosis pain.J. Minim. Invasive Gynecol. 2019; 26: S72https://doi.org/10.1016/j.jmig.2019.09.682
- Progesterone-dependent regulation of endometrial cannabinoid receptor type 1 (CB1-R) expression is disrupted in women with endometriosis and in isolated stromal cells exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).Fertil. Steril. 2012; 98 (948–956.e1)https://doi.org/10.1016/j.fertnstert.2012.06.009
- Cannabis treatments in obstetrics and gynecology: a historical review.J. Cannabis Ther. 2002; 2: 5-35https://doi.org/10.1300/J175v02n03_02
- Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation.Am. J. Pathol. 1927; 3 (93–110.43)
- The cannabinoid receptor CB1 contributes to the development of ectopic lesions in a mouse model of endometriosis.Hum. Reprod. 2017; 32: 175-184https://doi.org/10.1093/humrep/dew281
- The molecular connections between the cannabinoid system and endometriosis.Mol. Hum. Reprod. 2012; 18: 563-571https://doi.org/10.1093/molehr/gas037
- Increased rate of spontaneous miscarriages in endometriosis-affected women.Hum. Reprod. 2016; 31: 1014-1023https://doi.org/10.1093/humrep/dew035
- Risk for and consequences of endometriosis: a critical epidemiologic review.Best Pract. Res. Clin. Obstet. Gynaecol. 2018; 51: 1-15https://doi.org/10.1016/j.bpobgyn.2018.06.001
- Cannabis use, a self-management strategy among Australian women with endometriosis: results from a national online survey.J. Obstet. Gynaecol. Canada. 2020; 42: 256-261https://doi.org/10.1016/j.jogc.2019.08.033
- The immunopathophysiology of endometriosis.Trends Mol. Med. 2018; 24: 748-762https://doi.org/10.1016/j.molmed.2018.07.004
- Angiogenic factors in endometriosis.Ann. N. Y. Acad. Sci. 2002; 955: 89-100https://doi.org/10.1111/j.1749-6632.2002.tb02769.x
- [Endocannabinoids in the central nervous system].Med. Sci. (Paris). 2004; 20: 45-53https://doi.org/10.1051/medsci/200420145
- Endometriosis: current therapies and new pharmacological developments.Drugs. 2009; 69: 649-675https://doi.org/10.2165/00003495-200969060-00002
- Endometriosis.N. Engl. J. Med. 2020; 382: 1244-1256https://doi.org/10.1056/NEJMra1810764
Biography

Berkem Okten, MD, completed his Ob/Gyn residency at Trakya University. He then completed his education in assisted reproductive technologies (ART) at Istanbul Memorial Hospital, ART and Genetics Center. His main fields of scientific interest are ART, infertility and endometriosis. He is currently working at Acibadem Kozyatagi Hospital, IVF Center, Istanbul.
Article info
Publication history
Published online: January 30, 2023
Accepted:
January 24,
2023
Received in revised form:
December 29,
2022
Received:
November 7,
2022
Declaration: The authors report no financial or commercial conflicts of interest.Publication stage
In Press Journal Pre-ProofIdentification
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© 2023 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.