{"paper_id":"84615998-68e7-4c9c-9b2e-ece7082e414a","body_text":"Endometriosis is a chronic, inflammatory disease characterized by the presence of\nendometrial tissue outside the uterine cavity, affecting approximately 10% of women\nof reproductive age and often associated with infertility. Its main symptoms include\nchronic pelvic pain and dysmenorrhea. Treatment is challenging, and the use of\ncannabinoids, such as cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC), has shown\npromising therapeutic effects.\nThe hypothesis that the use of THC and CBD may bring benefits to patients diagnosed\nwith endometriosis should be considered. Thus, the objective of the present study\nwas to conduct a literature review on the therapeutic potential of Cannabidiol (CBD)\nand ∆9-Tetrahydrocannabinol (THC) in the signs and symptoms of endometriosis,\ninvestigating safety, dosage, and administration routes in humans.\n\nA bibliographic review study was performed. For the research, the search platforms\nPubMed, Scopus, and Embase were used, with descriptors established through DeCS/MeSH\nfor the first database and controlled vocabulary query for the other two.\nIn PubMed, the search strategy assembled was (Endometriosis[MeSH] OR Endometrioses OR\nEndometrioma OR Endometriomas) AND (Cannabidiol[MeSH] OR 1,3-Benzenediol,\n2-(3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl)-5-pentyl-, (1R-trans)- OR\nEpidiolex OR Cannabi* OR Resorcinols OR Terpenes OR “Dronabinol”[Mesh] OR THC OR\nTetrahydrocannabinol OR “Tetrahydrocannabinol, Trans-Isomer” OR\n“Tetrahydrocannabinol, Trans Isomer” OR Marinol) AND (“Therapeutic Uses”[MeSH] OR\n“Uses, Therapeutic” OR “Therapeutic Use” OR “Use, Therapeutic” OR “Therapeutic\nEffects” OR “Effects, Therapeutic” OR “Therapeutic Effect” OR “Effect,\nTherapeutic”), with 103 results obtained.\nIn Scopus, the research was conducted using (Endometriosis OR Endometrioses OR\nEndometrioma OR Endometriomas OR “adenomyosis externa” OR “endometriosis externa”)\nAND (Cannabidiol OR Epidiolex OR Cannabi* OR Resorcinols OR Terpenes OR Dronabinol\nOR THC OR Tetrahydrocannabinol OR “Tetrahydrocannabinol, Trans-Isomer” OR\n“Tetrahydrocannabinol, Trans Isomer” OR Marinol OR adversa OR reduvo OR relivar OR\nsyndros OR tetranabinex) AND (“Therapeutic Uses” OR “Uses, Therapeutic” OR\n“Therapeutic Use” OR “Use, Therapeutic” OR “Therapeutic Effects” OR “Effects,\nTherapeutic” OR “Therapeutic Effect” OR “Effect, Therapeutic” OR “drug treatment” OR\n“medicament therapy” OR “medicament treatment” OR “medicinal therapy” OR “medicinal\ntreatment” OR “pharmaceutical therapy” OR “pharmaceutical treatment” OR\n“pharmaco-therapy” OR “pharmaco-treatment” OR “pharmacological therapy” OR\n“pharmacological treatment” OR pharmacotherapy OR pharmacotreatment OR “therapeutic\nuses” OR “therapy, drug” OR “therapy, pharmacological” OR “treatment, drug” OR\n“treatment, pharmacological”), with 426 final results.\nFinally, in Embase, (‘adenomyosis externa’ OR ‘endometriosis externa’ OR\n‘endometriosis’) AND (‘2 (6 isopropenyl 3 methylcyclohex 2 en 1 yl) 5 pentylbenzene\n1, 3 diol’ OR ‘2 (6 isopropenyl 3 methylcyclohex 2 enyl) 5 pentylbenzene 1, 3 diol’\nOR ‘2 [3 methyl 6 (1 methylethenyl) 2 cyclohexen 1 yl] 5 pentyl 1, 3 benzenediol’ OR\n‘2 [3 methyl 6 (prop 1 en 2 yl) cyclohex 2 en 1 yl] 5 pentylbenzene 1, 3 diol’ OR ‘2\npara mentha 1, 8 dien 3 yl 5 pentylresorcinol’ OR ‘5` methyl 4 pentyl 2` (prop 1 en\n2 yl) 1`, 2`, 3`, 4` tetrahydrobiphenyl 2, 6 diol’ OR ‘a 1002 n5s’ OR ‘a1002n5s’ OR\n‘btx 1204’ OR ‘btx 1308’ OR ‘btx 1503’ OR ‘btx 1702’ OR ‘btx 1801’ OR ‘btx1204’ OR\n‘btx1308’ OR ‘btx1503’ OR ‘btx1702’ OR ‘btx1801’ OR ‘cardiolrx’ OR ‘epidiolex’ OR\n‘epidyolex’ OR ‘gwp 42003’ OR ‘gwp 42003p’ OR ‘gwp42003’ OR ‘gwp42003p’ OR\n‘nabidiolex’ OR ‘nantheia’ OR ‘oravexx’ OR ‘rad 011’ OR ‘rad011’ OR ‘trans\ncannabidiol’ OR ‘zygel’ OR ‘zyn 002’ OR ‘zyn002’ OR ‘cannabidiol’ OR ‘1 trans delta\n9 tetrahydrocannabinol’ OR ‘3 pentyl 6, 6, 9 trimethyl 6a, 7, 8, 10a tetrahydro 6h\ndibenzo [b, d] pyran 1 ol’ OR ‘6, 6, 9 trimethyl 3 pentyl 6a, 7, 8, 10a\ntetrahydrobenzo [c] chromen 1 ol’ OR ‘adversa’ OR ‘bx 1’ OR ‘bx1’ OR ‘delta 1 3, 4\ntrans tetrahydrocannabinol’ OR ‘delta 1 tetrahydrocannabinol’ OR ‘delta 1 trans\ntetrahydrocannabinol’ OR ‘delta 1, 2 tetrahydrocannabinol’ OR ‘delta 9\ntetrahydrocannabinol’ OR ‘delta 9 trans tetrahydrocannabinol’ OR ‘delta1 3, 4 trans\ntetrahydrocannabinol’ OR ‘delta1 cis tetrahydrocannabinol’ OR ‘delta1\ntetrahydrocannabinol’ OR ‘delta1 thc’ OR ‘delta1 trans tetrahydrocannabinol’ OR\n‘delta9 tetrahydro cannabinol’ OR ‘delta9 tetrahydrocannabinol’ OR ‘delta9 trans\ntetrahydrocannabinol’ OR ‘ea 1477’ OR ‘ea1477’ OR ‘l delta 9 trans\ntetrahydrocannabinol’ OR ‘levo delta 1 tetrahydrocannabinol’ OR ‘levo delta 9\ntetrahydrocannabinol’ OR ‘marinol’ OR ‘ppp 002’ OR ‘ppp002’ OR ‘qcd 84924’ OR\n‘reduvo’ OR ‘relivar’ OR ‘syndros’ OR ‘tetrahydrocannabinol 1 ene’ OR\n‘tetrahydrocannabinol delta1’ OR ‘tetrahydrocannabinol delta9’ OR ‘tetranabinex’ OR\n‘trans delta 9 tetrahydrocannabinol’ OR ‘u1 tetrahydrocannabinol’ OR ‘u9\ntetrahydrocannabinol’ OR ‘dronabinol’) AND (‘drug treatment’ OR ‘medicament therapy’\nOR ‘medicament treatment’ OR ‘medication’ OR ‘medicinal therapy’ OR ‘medicinal\ntreatment’ OR ‘pharmaceutical therapy’ OR ‘pharmaceutical treatment’ OR\n‘pharmaco-therapy’ OR ‘pharmaco-treatment’ OR ‘pharmacological therapy’ OR\n‘pharmacological treatment’ OR ‘pharmacotherapy’ OR ‘pharmacotreatment’ OR\n‘therapeutic uses’ OR ‘therapy, drug’ OR ‘therapy, pharmacological’ OR ‘treatment,\ndrug’ OR ‘treatment, pharmacological’ OR ‘drug therapy’), pointing to 30\nresults.\nAll published articles were included without restrictions on date, species, or\nlanguage. After the research, an analysis of all the articles found was conducted.\nThe selection was made based on the titles and abstracts obtained in the searches. A\ntotal of 9 papers were analyzed and discussed.\nEndometriosis is a chronic, inflammatory, and multifactorial disease,\ncharacterized by the presence of endometrial tissue outside the uterine cavity\nand very often associated with debilitating symptoms ( Febrasgo, 2021 ). Affecting approximately 10% of women of\nreproductive age, it can present with adhesions and fibrosis or even hormonal\nand immunological changes, resulting in infertility ( Tanbo & Fedorcsak, 2017 ). Studies indicate the presence\nof the disease in 25% to 50% of infertile women, with infertility occurring in\n30% to 50% of women with the disease ( Febrasgo,\n2021 ).\nAlthough the etiology of endometriosis remains unknown, several theories are\nconsidered on the subject. The primary one is described as the theory of\nretrograde menstruation, proposed in 1927 by John A. Sampson, which refers to\nthe occurrence of menstrual flow in the opposite direction of the natural\nprocess, leading to the consequent intraperitoneal implantation and adhesion of\nendometrial cells ( Sampson, 1927 ) ( D’Hooghe & Debrock, 2002 ). It is\nunderstood that there must also be the influence of genetic, hormonal, or\nenvironmental factors ( Nácul &\nSpritzer, 2010 ), as well as epigenetic factors ( Chen  et al ., 2023 ). Endometriosis is an\nestrogen-dependent pathology, aggravated by the presence of the hormone\nestradiol leading to increased inflammation, pain, and other signs and symptoms\n( Bulun  et al .,\n2012 ).\nThe most common symptoms involve chronic pelvic pain, dysmenorrhea, and\ndyspareunia, as well as tenesmus and hematochezia ( Horne & Missmer, 2022 ). Furthermore, the disease can be\nclassified as peritoneal, ovarian, and deep endometriosis, divisions that are\nrespectively characterized by the presence of superficial implants on the\nperitoneum, superficial implants on the ovary (including cysts and\nendometriomas), and lesions of depth equal to or greater than 5 mm in the\nretroperitoneal space or on the wall of pelvic organs ( Febrasgo, 2021 ).\nOne treatment alternative is the surgical removal of endometriotic foci through\nlaparoscopy, which is also the gold standard for diagnosing the disease, aiming\nto identify and remove existing lesions ( Mettler\n et al ., 2014 ). Pelvic ultrasound and pelvic\ncontrast-enhanced magnetic resonance imaging are exams that commonly support the\nsuspicion of some cases of the disease, sometimes also providing the diagnosis\n( Rolla, 2019 ). Several\npharmacological therapies are considered, such as the continuous use of\nprogestogens (e.g., Dienogest), combined oral contraceptives (COCs), or even\nnon-steroidal anti-inflammatory drugs (NSAIDs), aiming to treat signs and\nsymptoms and prevent recurrence after surgical intervention. Drugs act by\nreducing the action of estradiol on the endometrium, leading to a decrease in\ninflammation and angiogenesis, with possible reduction of endometriotic lesions\nand even anovulation. Conversely, combined contraceptives may help by promoting\nan increase in progesterone (related to the reduction of ectopic endometriotic\nfoci) and reducing ovarian estrogen production, in addition to anovulation. The\nmain concern regarding the off-label use of COCs for endometriosis relates to\nthe estrogen contained in the pill and its potential contribution to the\nprogression of the disease. The class of NSAIDs primarily acts by reducing\ninflammation and prostaglandin production by inhibiting related enzymes,\npotentially influencing pain ( Chen  et\nal ., 2023 ). Currently, depending on the patient’s\ncondition and medical approach, opioids may be preferred over NSAIDs, which is\nconcerning due to the drug class in question becoming a source of addiction,\nreinforcing the need for alternative pathways ( Allam  et al ., 2022 ).\nThe choice of treatment varies among patients, depending on their medical history\nand the severity of symptoms or even the desire to conceive during the period,\nsometimes requiring a combination of surgical and pharmacological intervention.\nIt is important to note that patients may exhibit progesterone resistance, which\ncan potentially impact the response to certain medications throughout the\ntreatment of endometriosis. Factors associated with inflammation, oxidative\nstress, epigenetics, disease phenotypes, and congenital characteristics\ninfluence such a response ( Donnez & Dolmans,\n2021 ). Moreover, women of childbearing age who desire to conceive\nneed to discontinue the use of hormonal therapies. Regarding cases requiring\nsurgical intervention, there is a known risk of adhesions and fibrosis after\nsurgery, that could lead to infertility due to tubal factor, and the risk of\ndecreased ovarian reserve in cases of surgical reduction of ovarian endometrioma\n( Chen  et al ., 2023 ).\nThere is generally a significant delay in diagnosis, which directly impacts the\nquality of life of affected patients ( Horne\n& Missmer, 2022 ).\nThe cannabis plant, according to geographical and evolutionary studies,\noriginated millions of years ago, and by 4000 BCE, it was already being\nexploited as a source of fibers and food, as well as serving medicinal purposes\nand in rituals. In the 19th century, the physician William Brooke O’Shaughnessy\nconducted the first study demonstrating the pharmacological and toxicological\nproperties of the plant. He also noticed differences between those cultivated in\nIndia (C.  indica ) and Europe (C.  sativa ) and\nevaluated their use in some of his patients, where he discovered analgesic and\nmuscle-relaxing properties and explored their application in palliative care.\nSubsequently, in the 20th century, there was the discovery of the\nendocannabinoid system, its receptors, and the endogenous molecules that act on\nit, which renewed scientific interest in the properties of the plant ( O’Shaughnessy, 1839 ) ( Pisanti & Bifulco, 2019 ).\nThe endocannabinoid system (ECS) is made up of endogenous ligands, G\nprotein-coupled membrane receptors (GPCRs), and enzymes to degrade the ligands.\nTo date, two G-protein couplings related to this system have been identified, as\nwell as two endogenous ligands (arachidonoyl ethanolamide and 2-arachidonoyl\nglycerol). The ECS works through a mechanism in which the carrier protein\ntransports endocannabinoids retrograde from postsynaptic cell membranes to bind\nto cannabinoid receptors present on the presynaptic membrane, where they are\ndegraded by the FAAH or MAGL enzymes. The half-life of endocannabinoids is very\nshort, as they modulate the release of neurotransmitters by inhibiting the\ninflux of intracellular calcium and are quickly reabsorbed and catabolized.\nUntil the latest research, two types of signaling in the ECS were recognized,\nphasic signals and tonic signals. The tonic signals are known as basal\nsignaling, responsible for endocannabinoid tone, while the phasic signals are\nresponsible for the change in eCBs levels over time ( Silver, 2019 ).\nCannabinoids, substances responsible for activating cannabinoid receptors, can be\nderived from the plant (phytocannabinoids), synthetic, or endogenous\n(endocannabinoids). The main cannabinoid receptors, known as cannabinoid\nreceptors 1 and 2 (CB 1  and CB 2 , respectively), are coupled\nto G protein, and the tissue distribution of these receptors is related to the\nconsequent effects of interactions ( Klein,\n2005 ). The endocannabinoid system, present in all animals (including\nvertebrates and invertebrates, but in different forms), was discovered after the\nstructural knowledge of ∆9-tetrahydrocannabinol (THC). It is known that\nCB 1  and CB 2  receptors are related to various\nbiological processes such as pain, anxiety, inflammation, immune function,\nmetabolic regulation, and others. While CB 1  is mainly located in the\ncentral nervous system, CB 2  is found mainly in cells of the immune\nsystem, spleen, and tonsils. In humans, CB 1  receptors are\nsignificantly absent in the brainstem or spinal cord, which ensures safety in\nrelation to vital functions. It is also known that CB 2  receptors\nmodulate cytokine release ( Silver,\n2019 ).\nThe Cannabis sativa plant is known worldwide for its medicinal and psychoactive\nproperties, with more than 500 identified compounds, including cannabinoids,\nflavonoids, terpenes, and fatty acids ( Alves\n et al ., 2020 ). Among the various cannabinoids\npresent in the plant, cannabidiol (CBD) and THC ( Urits  et al ., 2020 ) are noteworthy. Both have\nmedicinal properties; however, unlike CBD, THC induces psychoactive effects\n( Reich  et al .,\n1982 ). THC acts as a partial agonist of CB 1  and CB 2 \nreceptors, with activation or blockade of their activity by other cannabinoids\ndepending on their level of expression and binding efficiency. CBD exhibits\ninverse agonism to CB 2  ( Thomas\n et al ., 2007 ) and acts as an antagonist to\nCB 1  and CB 2  receptor agonists. Although it expresses\nlow affinity for the receptors, it can interact at low concentrations ( Pertwee, 2008 ). There is also significant\ninteraction of CBD with transient receptor potential vanilloid 1 and 2 (TRPV1\nand TRPV2) receptors, a fact related to the pharmacodynamic properties of the\nsubstance. TRPV2 is associated with analgesia ( Jîtcă  et al ., 2023 ).\nThe THC molecule was identified in 1964 and has well-known therapeutic\nproperties, with a complex and dose-dependent effect ( Pernoncini & Oliveira, 2014 ). The principal therapeutic\neffects are antiepileptic, antiemetic, antispasmodic, analgesic properties, etc.\nIt can present adverse effects, such as influencing the ability to discriminate\ntime intervals and memory, as well as inducing disconnected thoughts,\nhallucinatory experiences, and others ( Carlini,\n2004 ). In contrast, the first studies demonstrating the medicinal\npotential of CBD emerged in 1982, where a protective effect against THC-induced\npsychoses was demonstrated. Subsequent studies revealed effects such as\nanxiolytic, anticonvulsant, antiemetic, anti-inflammatory, antioxidant,\nimmunosuppressive, antiproliferative, pro-apoptotic, antiangiogenic, and others\n( Pernoncini & Oliveira, 2014 ). In\nrelation to chronic pain, a symptom that affects about 20% of the population,\nCBD is a great candidate for use in treatment, although its analgesic effects\nare not yet fully understood ( Urits  et\nal ., 2020 ).\nDmitrieva  et al . (2010) \nreported one of the first published articles on the subject, involving the role\nof the endocannabinoid system in endometriosis. Through a model using rats, the\nexpression of CB 1  receptors in the innervation of endometriotic foci\nwas identified, as well as the reduction of hyperalgesia associated with the\ndisease by CB 1  receptor agonists. The research group also indicated\nthat there is higher expression of the CB 1  receptor in endometriotic\nlesions compared to the healthy uterus of the same rats, facts that suggest that\ntreatments aimed at activating these receptors (either directly through\nCB 1  agonists or indirectly by increasing endocannabinoid levels)\ncan be performed with low impact on uterine function ( Dmitrieva  et al ., 2010 ).\nIn the same year, Leconte  et al.  evaluated the antiproliferative\nand antifibrotic effects  in vitro  and  in vivo \nof a cannabinoid agonist (WIN 55212-2) in deep endometriosis. The  in\nvitro  model was conducted using primary cultures of endometrial and\ndeep endometriotic cells extracted from patients with or without the disease,\nwhile the  in vivo  model was conducted in mice by implanting\ndeep infiltrating endometriotic nodules removed from human patients. They\nevaluated the presence of CB 1  and CB 2  receptors by\ncomparing eutopic endometrial cell lines and deep endometriotic lesions. The\ncell lines were treated with increasing concentrations of the cannabinoid\nagonist, and a dose-dependent reduction in cell proliferation was observed.\nAdditionally, they demonstrated that the treatment did not exhibit cytotoxicity\nat the studied concentrations and that there was a reduction in the production\nof reactive oxygen species (ROS). Furthermore, the inhibition of smooth muscle\nalpha-actin (αSMA) expression is related to the antifibrotic properties\nof the tested substance. The results were reproduced in the  in\nvivo  model, and thus, the treatment was considered promising for\nfurther studies ( Leconte  et\nal ., 2010 ).\nAllam  et al . (2022) \nstudied the expression of CB 1  and CB 2  receptors in ovarian\nendometriotic lesions. They determined, through immunohistochemistry,\nimmunoblotting, and gene expression studies, the intense presence mainly in\nepithelial cells of such lesions. They also demonstrated increased expression of\nthese receptors in ovarian endometriotic lesions compared to surrounding stromal\ntissues. Finally, the study suggested investigating the use of CB 2 \nreceptor agonists in the treatment of inflammation and pain related to ovarian\nendometriosis, given their relationship with cellular processes ( Allam  et al. , 2022 ).\nA study was conducted on the exposure to THC in female mice with induced\nendometriosis, evaluating the effects associated with nociception, cognition,\nand emotion. THC treatment reduced hypersensitivity in a dose-dependent manner,\nparticularly at 2 mg/kg/day, without impairing memory or inducing anxiety-like\nbehavior. Long-term treatment (32 days) inhibited the development of\nendometriotic cysts, with no changes observed in the uterine or eutopic\nendometrial areas. The findings suggest that THC may selectively target ectopic\nendometrial cells and could have potential therapeutic effects for managing\nendometriosis-related pain and inflammation ( Escudero-Lara  et al ., 2020 ).\nGenovese  et al . (2022) \nstudied the anti-inflammatory, antioxidant, and analgesic effects of CBD related\nto endometriosis through an  in vivo  model in rats. The animals\nwere divided into two groups, then classified as donors and recipients. The\ndonors received intraperitoneal injections of exogenous gonadotropin (PMSG) to\ninduce estrogen levels and were subsequently euthanized to remove the uterus and\ndissect the extrauterine tissue. The recipients, on the other hand, received\nintraperitoneal injections with a solution containing the tissue, aiming to\ndevelop the lesion in the region. Among the recipients, they were divided into\nthree groups, being in order: endometriosis group; endometriosis + CBD group;\nand sham group. The first one received vehicle (ethanol/Tween 80/0.9% saline\n(3:1:16)), the second group received 10 mg/kg of CBD, and the third group\nreceived an intraperitoneal injection of phosphate buffered saline (PBS) in the\nmidventral area as a substitute for endometrial tissue. Behavioral,\nhistological, enzyme-linked immunosorbent assays, and measurements of levels of\nvarious neurosensitizing and pro-inflammatory substances were performed. They\nobserved anti-inflammatory and antiproliferative effects regarding the size of\nthe lesion and peritoneal fluids, as well as a decrease in neurogenic\ninflammation and neurosensitizing mediators ( Genovese  et al ., 2022 ).\nOkten  et al . (2023)  also\nstudied the effects of CBD in an animal model. The experiments used rats, which\nwere divided into four groups (saline solution, CBD 5mg/kg, CBD 20mg/kg, and\nleuprolide acetate), all undergoing three laparotomies, with intervals of 21\ndays. The first involved the induction of endometriotic lesions with tissue\ntransplanted from the animal itself. The second aimed to confirm the formation\nof the implants and measure them, allowing injections according to the\npreviously determined distribution. Finally, the third surgery was performed to\ncollect samples of peritoneal fluid, in addition to measuring and collecting the\nimplants, followed by euthanasia of the animals and collection of intracardiac\nserum samples. In the group that received CBD at a lower concentration,\nsignificant reductions were observed in the areas of the implanted endometriotic\nlesions compared to the group treated with saline, as well as in the levels of\ntotal antioxidant status (TOS), oxidative stress index (OSI), interleukin-6\n(IL-6), and tumor necrosis factor-alpha (TNF-α), along with an increase\nin total antioxidant status (TAS) ( Okten\n et al ., 2023 ).\nIn studies involving humans, the prevalence, tolerability, and self-reported\nefficacy of Cannabis in women with endometriosis in Australia were evaluated. A\nquestionnaire was administered to female individuals between 18 and 45 years old\nwho had a surgically confirmed diagnosis of the disease. Various symptoms were\naddressed, including anxiety, depression, fatigue, gastrointestinal problems,\nnausea and vomiting, dyspareunia, dysuria, and sleep, in addition to pelvic pain\nand its impacts. They also inquired about costs, frequency of use (25% - less\nthan once a week; 12.5% - once a week; 18.75% - two to three times a week;\n43.75% - daily or several times a day), adverse events (10.42% - reported\noccurrence; 89.58% - did not report occurrence), and routes of administration\n(50% - smoking; 11.9% - vaporization; 11.9% - oral/edible; 2.38% - rectal or\nvaginal oil; 23.8% - multiple). Among the participants, 56% of women using the\nsubstance reported a significant reduction in medication use. The main\nimprovements noted by the participants were related to pelvic pain and sleep,\nanxiety, depression, nausea/vomiting, and gastrointestinal symptoms. Reported\nadverse events included drowsiness, anxiety, and tachycardia. Participants who\nreported the use of medicinal cannabis had higher scores for the impact of\npelvic pain compared to those who did not use it. The proportions of THC/CBD in\nthe products consumed by the participants were not evaluated, and the reasons\nwhy participants consumed cannabis and/or other treatments were not explored\n( Sinclair  et al .,\n2020 ).\nSinclair  et al . (2021) \nstudied the effects of cannabis ingestion on pelvic pain associated with\nendometriosis and other associated symptoms. The study was a retrospective\ncohort analysis using electronic records from users of a Canadian app for\nmonitoring medicinal cannabis use. Statistical analysis of the data was\nperformed, and self-rated efficacy was defined based on the initial and final\nclassifications of reported symptoms. Self-reported symptoms were classified as\npain (pelvic pain and dysmenorrhea), gastrointestinal (pain and nausea), and\nmood (depression and low libido), while forms of administration were divided\ninto oral (edible, oil, capsule, spray), topical (transdermal and topical), and\ninhaled (vaporized and smoked, puffs). The mean age obtained was 35 years, with\nadministrations mainly pulmonary (inhaled) and use mainly related to pelvic\npain. The doses used ranged from 9mg/mL to 1mg/mL, as well as the concentrations\nof THC and CBD, both according to the chosen route of administration ( Sinclair  et al .,\n2021 ).\nSinclair  et al . (2022) \nstudied the use of cannabis in the treatment of endometriosis, with a larger\nsample of patients. The eligible participants were those who had confirmed\nendometriosis and have a history of using cannabis or products based on it for\nsigns and symptoms control in the preceding three months. They inquired about\nthe symptoms present at that moment (most of them being fatigue, chronic pelvic\npain, and intestinal symptoms) and the medications/treatments being used at the\ntime and, also, the access to Cannabis. The cessation or significant reduction\nof other medications while using cannabis was reported. The reasons for using\ncannabis were since inadequate pain control with other medications, intolerable\nside effects of other medications, perception of effects on signs and symptoms\nduring recreational use, recommendations from colleagues/support groups, medical\nrecommendation, difficulty accessing other medications, difficulty accessing\nsurgery, and delayed/canceled surgery due to the COVID-19 pandemic. A\nsignificant number of participants reported that they would continue to use\nmedicinal cannabis because it provided better effects in terms of pain relief\ncompared to other current treatments. When questioned about communication and\ndiscussion of the use with healthcare professionals, generally there was no\nknowledge about legal access routes and no communication to doctors due to\nconcerns related to legal and social issues, which poses risks to individuals’\nhealth due to possible pharmacodynamic interactions and systemic effects. The\ngroup considered it a public health issue due to the widespread use of illicit\ncannabis, as it does not provide guaranteed quality and standardization of\nnecessary active cannabinoids for regulation, nor does it provide significant\nsafety for consistent clinical reproducibility, and it carries risks of\ncontamination (mold, heavy metals, bacteria, and pesticide residues) ( Sinclair  et al .,\n2022 ).\nFurthermore, there are already some studies in the development phase registered\nat the National Library of Medicine, such as  NCT05670353  (São Paulo,\nBrazil) and  NCT04527003  (Pennsylvania, United States of America) ( ClinicalTrials.gov, 2023 ).\n\nBased on the findings above, several studies already indicate the therapeutic\npotential of cannabinoids ∆9-tetrahydrocannabinol and cannabidiol in the treatment\nof chronic pelvic pain, inflammation, cell proliferation, and other signs and\nsymptoms directly associated with endometriosis. Clinical trials are needed to\nconfirm the efficacy and safety of treatment in humans, also evaluating side\neffects, dosage, route of administration, and others.","source_license":"public-domain-us","license_restricted":false}