{"paper_id":"709907d5-8d2e-4379-a666-8985a0be7356","body_text":"Vol.:(0123456789)\nDrugs (2023) 83:1571–1579 \nhttps://doi.org/10.1007/s40265-023-01951-z\nCURRENT OPINION\nThe Place of Cannabinoids in the Treatment of Gynecological Pain\nJustin Sinclair1  · Jason Abbott2,3 · Andrew Proudfoot1 · Mike Armour1,4,5 \nAccepted: 20 September 2023 / Published online: 13 October 2023 \n© The Author(s) 2023\nAbstract\nCannabis sativa (L), a plant with an extensive history of medicinal usage across numerous cultures, has received increased \nattention over recent years for its therapeutic potential for gynecological disorders such as endometriosis, chronic pelvic \npain, and primary dysmenorrhea, due at least in part to shortcomings with current management options. Despite this grow -\ning interest, cannabis inhabits an unusual position in the modern medical pharmacopoeia, being a legal medicine, legal \nrecreational drug, and an illicit drug, depending on jurisdiction. To date, the majority of studies investigating cannabis use \nhave found that most people are using illicit cannabis, with numerous obstacles to medical cannabis adoption having been \nidentified, including outdated drug-driving laws, workplace drug testing policies, the cost of quality-assured medical can-\nnabis products, a lack of cannabis education for healthcare professionals, and significant and persistent stigma. Although \ncurrently lacking robust clinical trial data, a growing evidence base of retrospective data, cohort studies, and surveys does \nsupport potential use in gynecological pain conditions, with most evidence focusing on endometriosis. Cannabis consumers \nreport substantial reductions in pelvic pain, as well as common comorbid symptoms such as gastrointestinal disturbances, \nmood disorders such as anxiety and depression, and poor sleep. Substitution effects were reported, with >50% reduction or \ncessation in opioid and/or non-opioid analgesics being the most common. However, a substantial minority report not disclos-\ning cannabis consumption to their health professional. Therefore, while such deprescribing trends are potentially beneficial, \nthe importance of medical supervision during this process is paramount given the possibility for withdrawal symptoms.\nPlain Language Summary\nCannabis, whether purchased illicitly, or obtained through legal means, is commonly used by those with chronic pelvic pain, \nespecially people with endometriosis. People report several benefits from using cannabis, including being able to reduce \ntheir normal medications including opioid based painkillers, but often don’t tell their health professional about this. This \ncould lead to issues with withdrawal symptoms, so clinicians should be aware of the high prevalence of use of cannabis in \nthis population.\n * Justin Sinclair \n 19948081@student.westernsydney.edu.au\n * Mike Armour \n M.Armour@westernsydney.edu.au\n1 NICM Health Research Institute, Western Sydney \nUniversity, Sydney, NSW, Australia\n2 Division of Obstetrics and Gynaecology, School of Clinical \nMedicine, Medicine and Health, UNSW, Sydney, NSW, \nAustralia\n3 Gynaecological Research and Clinical Research (GRACE) \nUnit, Royal Hospital for Women, UNSW, Sydney, NSW, \nAustralia\n4 Translational Health Research Institute, Western Sydney \nUniversity, Sydney, NSW, Australia\n5 Medical Research Institute of New Zealand (MRINZ), \nWellington, New Zealand\nKey Points \nRobust clinical trial data is currently lacking for gyneco-\nlogical pain conditions.\nDespite this, cannabis is being used to treat gynecologi-\ncal pain, especially in those with endometriosis or other \nforms of chronic pelvic pain, with reductions in symp-\ntoms such as pelvic pain commonly reported.\nCannabis consumption for gynecological pain should be \nundertaken under medical supervision, especially when \nreducing pharmaceutical interventions like opioids.\n\n1572 J. Sinclair et al.\n1 Introduction\nCurrent global estimates suggest 39.6% of women and those \nassigned female at birth* (hereafter denoted as women)—or \napproximately 1.53 billion people, live with gynecological \ndisease [1], with pain often a key symptom. The most com-\nmon causes of gynecological pain are primary or secondary \ndysmenorrhea, with over 70% of women reporting dysmen-\norrhea (period pain) at some stage of their life [2 ]. Primary \ndysmenorrhea is defined as menstrual pain in the absence of \nunderlying structural changes [3]. Primary dysmenorrhea’s \ncharacteristic symptom is crampy, colicky spasms of pain in \nthe suprapubic area, occurring within 8–72 h of menstrua-\ntion and peaking within the first few days as menstrual flow \nincreases [3, 4]. In addition to painful cramps, many women \nwith primary dysmenorrhea experience other menstrual-\nrelated symptoms, including back and thigh pain, headaches, \ndiarrhea, nausea, and vomiting [4]. The largest contributing \nphysiological factor in primary dysmenorrhea is increased \namounts of prostaglandins present in the menstrual fluid [5]. \nIf there is no pregnancy after ovulation, progesterone levels \ndecline in the late luteal phase of the cycle. Reduction in \nprogesterone levels destabilizes cell membranes in endo-\nmetrial tissue and causes the hydrolyzation of cell mem-\nbrane phospholipids (mainly omega-6) to form arachadonic \nacid. Arachadonic acid is converted via the cyclooxygenase \npathway to prostaglandins PGE2 and PGF2a [5 , 6]. These \nexcess prostaglandins are released when the endometrial lin-\ning breaks down during menses. Prostaglandins, especially \nPGF2a, stimulate myometrial contractions, reducing uterine \nblood flow and causing uterine hypoxia. This is responsible \nfor the painful cramping that characterizes primary dysmen-\norrhea [5 , 7]. Secondary dysmenorrhea is menstrual pain \nassociated with structural changes in the pelvis or an identifi-\nable cause such as endometriosis [4]. In Australia and other \nhigh-income countries, persistent dysmenorrhea is reported \nin over 90% of women and girls under age 25 years [8 , 9]. \nDysmenorrhea may lead to absenteeism at work [10], and \naffect attendance and academic performance both at school \nand in tertiary education [2 ], with many people reporting \ninadequate symptom management [11–13].\nChronic pelvic pain (CPP), defined as pain in the pel-\nvis for > 6 months’ duration that is severe enough to cause \nfunctional disability or require medical intervention [14] is \na common type of gynecological pain [15– 17]. CPP may \nbe cyclic, non-cyclic or both [ 18] and commonly includes \ndysmenorrhea (period pain), non-cyclical pelvic pain, dys-\npareunia (painful intercourse), dysuria (pain on urination), \nand dyschezia (pain on defecation) [19]. CPP affects one in \nfour women (26%) [18, 20], accounting for 40% of laparos-\ncopies, 10% of specialist gynecology consultations, and 12% \nof hysterectomies in the USA annually [18]. CPP includes \nconditions such as endometriosis, adenomyosis, vulvodynia, \ninterstitial cystitis, and bladder pain syndrome [19, 21, 22], \nwith endometriosis the single most prevalent disease in this \ngroup [23]. Symptom management is frequently challenging \ndue to involvement of neuropathic, nociplastic, and nocicep-\ntive pain pathways [21].\nCurrent management strategies for gynecological pain \ndepend on its underlying cause. Primary dysmenorrhea is \ncommonly managed by non-steroidal anti-inflammatory \ndrugs (NSAIDs) and/or the oral contraceptive pill as first-\nline treatment(s) [24], however a significant number of \nwomen report less than optimal symptom management, \nwith 25% of those using ibuprofen and 35% of those using \nparacetamol reporting no reduction in dysmenorrhea sever-\nity [12]. This may explain why women are open to using \nother treatments such as cannabis to manage their primary \ndysmenorrhea symptoms [13]. Current treatments for endo-\nmetriosis and chronic pelvic pain are generally considered \nsuboptimal by those with the disease [15, 25], with only \n25% of those with endometriosis being satisfied with their \nsymptom management [25]. There are concerns about lack \nof effectiveness and problematic side effects of many medi-\ncations for pelvic pain, leading to discontinuation rates of \n25–50% [26]. Opioid analgesics are not recommended for \nchronic pelvic pain due to both a lack of efficacy and safety \nconcerns with respect to ongoing use [27]. However, despite \nthis they continue to be prescribed; women with endometrio-\nsis have a four times greater risk of chronic opioid use com-\npared with women with no endometriosis [28]. For those \nwith endometriosis, surgery is considered the gold standard \nbut often has significant costs, long waiting times [29], and \nsubstantial recurrence rates, even with expert endometriosis \nsurgeons [30].\nGiven the prevalence of gynecological pain, its delete-\nrious effect on quality of life, and the current difficulties \nin managing this pain, finding effective, safe interventions \nwith low addictive/dependence potential is identified as an \ninternational priority [31– 33].\n2  Historical Use of Cannabis\nCannabis sativa is one of the oldest cultivated plants utilized \nby humans, being used as a food, textile and as a medicine \nfor millennia [34–36]. The Ebers Papyrus (1550 BCE) from \nancient Egypt describes the use of cannabis to aid child -\nbirth [37]. In ancient China, the use of cannabis for female \nreproductive symptoms was reported in the Pen-Tsao Ching, \nbased on the oral traditions passed down from the Emperor \nShen-Nung, who lived circa 2700 BCE [36, 38]. The age-\nold Indian Atharva Veda of 1000 BCE described cannabis \nas a sacred plant, used as an analgesic, anesthetic, anti-\ninflammatory, anti-spasmodic, and hypnotic medicine [36]. \n\n1573\nCannabis for Gynecological Conditions\nMore recently, the Chinese Bencao Gang Mu compiled in \n1596 recommended cannabis flowers for menstrual disorders \n[37], the Persians utilized it for calming uterine pains [37], \nAfrican cultures utilized it to facilitate childbirth, and South \nAmerican cultures reported its utility for menstrual cramps \nin the 16th century [36].\nCannabis was introduced to Western medicine in 1842 \nby the Irish physician O’Shaughnessy [37]. Soon after, it \nwas acknowledged in the Dispensatory of the United States, \nand tinctures of cannabis were prescribed to manage uter -\nine hemorrhage [39], assistance in childbirth [40], neuralgic \ndysmenorrhea [41], hyperemesis gravidarum, dysmenorrhea, \nand heavy menstrual bleeding—the latter being published \nin the British Medical Journal [ 37, 42]. In the 19th cen-\ntury, cannabis was also prescribed as an anodyne in chronic \nmetritis, endometritis, and chronic cystitis [37]. Importantly, \ncannabis was found to have advantages over opiates for \npain [43], and could also be useful for opiate withdrawal \n[44–46]. Notwithstanding its widespread popularity, can-\nnabis started falling out of favor as a medical treatment in the \nearly 20th century, due mainly to a lack of quality assurance \nand standardization from imported material [47]—factors \nthat were being addressed by the newly birthed pharmaceu-\ntical industry and its single active drug model. However, \nwith the implementation of the Marihuana Tax Act in 1937 \n[48], which effectively criminalized the possession and use \nof cannabis as a medicine in the US, widespread medical \nuse largely ceased. Cannabis was subsequently removed \nfrom the United States Pharmacopoeia in 1942 and was \nadded to the United Nation’s Single Convention on Narcotic \nDrugs in 1961. Cannabis was prohibited through the US \nControlled Substances Act of 1970 where it was classified \nas a Schedule 1 controlled substance—defined as having \nno accepted medicinal use, high abuse potential, and con-\ncerns for dependence [48]. Whilst history suggests that the \ndrivers for this prohibitionist position were more idealistic \nthan evidence-based [49, 50], the fact remains that Cannabis \nsativa remains a largely prohibited substance globally, with \nchanges to legislation only relatively recently allowing for \nmedicinal use in a growing number of nations.\nDespite decades of prohibition and Schedule 1 relegation, \nresearch into the therapeutic potential of cannabis continued \nlargely unabated, with two of the main active constituents \nof cannabis, the terpeno-phenolic cannabinoids cannabidiol \n(CBD) and delta-9-tetrahydrocannabinol (THC) discovered \nin 1940 and 1964, respectively [51, 52]. Cannabidiol, a non-\nintoxicating cannabinoid, has a wide range of pharmaco -\nlogical activities, including neuroprotective, anti-convulsant, \nanxiolytic, analgesic, anti-depressant, antioxidant, and anti-\ninflammatory properties [53– 58]. THC also has a broad \narray of pharmacological actions, including analgesic, anti-\nemetic, anti-inflammatory, muscle relaxant, and sedative \nproperties [59–62]—all of which can be of potential benefit \nto gynecological pain conditions, but must be balanced with \nits intoxicating effects. To date, there are over 144 different \ncannabinoids identified across the Cannabis genus [63], with \nresearch ongoing into their pharmacological activities and \npotential benefit in human health. Additional research has \nalso identified an entire neuromodulatory system within the \nbody—the endocannabinoid system (ECS)—with receptors \nidentified in most organ systems, including the female repro-\nductive system, resulting in various changes to physiological \nprocesses [64].\n3  Mechanisms of Action\nThe ECS consists of G-protein coupled receptors (i.e., Can-\nnabinoid 1 and 2 receptors), endogenous ligands (i.e., the \nendocannabinoids), and ligand metabolic enzymes [65] \nresponsible for the synthesis and degradation of endocan-\nnabinoids. More broadly, the ECS is involved in the mod-\nulation of a host of physiological responses, inclusive of \ninflammation, nociception, appetite regulation, respiration, \nand metabolism [66], with more recent research highlighting \nECS involvement across many aspects of the female repro-\nductive system. The ECS engages in a complex interplay \nwith the hypothalamic pituitary ovarian (HPO) axis to exert \ncontrol over certain female reproductive processes [67], \nincluding pain modulation, oocyte maturation, ovarian endo-\ncrine secretion, folliculogenesis, uterine decidualization and \nplacentation, implantation, and embryo transport [67– 69]. \nResearch into the role of ECS in gynecological conditions \nhas highlighted that elevated systemic levels of endocan-\nnabinoids (i.e., anandamide and 2-arachidonoyl glycerol \n[2-AG]), along with decreased local cannabinoid 1 receptor \n(CB1) expression are present in people with endometriosis \n[70], and that the ECS may be a promising target to address \nendometriosis-related pain [71–73]. Furthermore, alterations \nin ECS homeostasis may lead to dysfunctional modulation \nof cellular processes involved in reproductive pathologies, \nnamely pre-eclampsia, miscarriage, and ectopic pregnancy \n[74]. Research also posits that ECS dysfunction is involved \nin the pathogenesis of dysmenorrhea in adenomyosis [75].\nProposed mechanisms by which both endocannabinoids \nand cannabinoids exert analgesic effect across gynecologi-\ncal pain and associated disorders are numerous and inter-\nrelated. Neural and non-neural cells produce arachidonic \nacid derivatives known as endocannabinoids in response to \ntissue injury [76]. These endocannabinoids, mainly anan-\ndamide and 2-AG, modulate neural pain signal conduction \nby mitigating sensitization and inflammation via activation \nof cannabinoid receptors, which are also targets for phyto-\ncannabinoids such as THC [77, 78]. Cannabinoid 1 (CB1) \nreceptors are predominantly expressed throughout the cen-\ntral nervous system where they modulate neurotransmitter \n\n1574 J. Sinclair et al.\nrelease; however, they are also present in the pain-modu-\nlating areas such as the dorsal root ganglion [ 78], periaq -\nueductal grey, and rostral ventral medulla [ 79, 80]. Addi -\ntionally, CB1-mediated analgesia is not solely via nervous \nsystem modulation, but also potentiates anti-inflammatory \neffects on mast cells [81]. Cannabinoid 2 (CB2) receptors \nare widely expressed in high concentrations throughout the \nperiphery and immune cells [80], but are also found in lower \namounts in the brain and spinal cord [78]. CB2 receptors \nincrease in response to peripheral nerve damage, interfere \nwith inflammatory hyperalgesia, and modulate neuroim-\nmune activity [78, 82]. Furthermore, CB2 activation inhibits \nproinflammatory signaling released near nociceptive nerves \nand can propagate downstream release of opioids [81, 83], \nand has demonstrated antinociceptive activity in inflamma-\ntory hyperalgesia and neuropathic pain [84, 85].\nFocusing on endometriosis as an exemplar, there are sev-\neral drivers for the pain experience, including nociceptive, \ninflammatory, and neuropathic pain mechanisms which are \ninterconnected and complex to manage [ 73]. Additionally, \nthe psychological impact of the pain experience in people \nwith endometriosis can cause anxiety and pain catastrophiz-\ning, with the related sequalae of impacting self-esteem and \nrelationships, worsening the pain experience further [ 73]. \nPhytocannabinoids from Cannabis spp not only interact \nwith CB1 and CB2 receptors to exert analgesic activity, but \nalso modulate transient receptor potential vanilloid (TRPV) \nchannels which are involved in neuropathic pain signals \n[81, 86]. Modulation of serotonin receptors (5HT1A) by \nphytocannabinoids such as cannabidiol can assist in pain \nthrough exerting anxiolytic and antidepressant activity, and \nother antinociceptive effects of cannabinoids have been pro-\nposed specific to endometriosis, including antiangiogenic, \nimmunomodulating, and antiproliferative activities [81, \n87, 88].Whilst more research is needed to fully elucidate \nthe efficacy and safety of cannabis and cannabinoid-based \nmedicinal products in endometriosis and other gynecologi-\ncal conditions, recent changes in regulatory scheduling of \ncannabis has opened up this field of research to the broader \ninternational scientific community.\n4  Access to Medicinal Cannabis\nWith the enactment of the Compassionate Use Act (Propo-\nsition 215) in 1996, California became the first US state \nto permit legal access to cannabis for medical reasons \nunder physician supervision [48]. This started a ripple \neffect throughout the USA, with 37 states allowing legal-\nized medicinal cannabis, including seven states allowing \naccess to CBD-containing products only. In contrast, Canada \nadopted the Marijuana Medical Access Regulations in 2001 \nthat was replaced by the Marijuana for Medical Purposes \nRegulations in 2014 with no restrictions on the clinical indi-\ncations for which cannabis could be prescribed [89]. More \nthan 50 countries have followed suit, adopting assorted \nmedicinal cannabis regulatory models [90], including Israel, \nthe United Kingdom, Australia, and New Zealand. Different \nnations have varying degrees of regulatory oversight and \nproduct quality assurance standards. Changes to laws and \nregulations have also allowed the scientific community to \nresearch cannabis more rigorously and allowed people with \ngynecological pain to access cannabis legally for medicinal \npurposes.\n5  Evidence for Gynecological Pain \nConditions\nCurrently there are few properly designed and controlled \nrandomized clinical trials investigating the efficacy of can-\nnabis for gynecological symptoms, which limits clear guid-\nance around clinical recommendations. Until such studies \nare undertaken, there is a reliance on evidence that is lower \non the evidence pyramid, supported by a growing body of \nretrospective data, cohort studies, and surveys, reporting \nthe positive effects of cannabis from patients with gyneco-\nlogical symptoms [91]. Given poor symptom management \n[15], long waiting times for endometriosis surgery in some \njurisdictions [29], and side effects of many medications for \npelvic pain [26], it is perhaps unsurprising that people with \nCPP are using cannabis as a substitute for, or in addition to, \nmore orthodox treatments. A cross-sectional survey of 240 \nCPP patients recruited in an outpatient gynecology office \nreported that one-quarter of patients with CPP used can -\nnabis regularly as an adjunct to prescribed medicines, with \n96% reporting improvements in their symptoms, including \n84% reporting improved muscle pain, 72% a reduction in \nirritability, depression, and anxiety, and 68% an improve-\nment in sleep [92]. Similarly, a cross-sectional survey of 484 \nendometriosis patients in Australia on self-management of \nendometriosis reported illicit cannabis was the most effec-\ntive self-management strategy [93]. In this survey, one in \nten respondents reported utilizing illicit cannabis for thera-\npeutic purposes to manage their endometriosis symptoms, \nwith self-reported pain reduction rated at 7.6/10. In addi-\ntion, over half (56%) of the cohort reported a 50% or more \nreduction in pharmaceutical medications typically used for \nendometriosis management [ 93, 94]. From a retrospective, \nelectronic record-based cohort study of 252 patients with \nself-reported endometriosis, cannabis use for decreasing \npelvic pain was described, with inhaled delivery being the \nmost common mode of administration [95]. This prefer -\nence for inhalation may be due to the rapid speed of onset \nof pharmacological effects for inhaled cannabis compared \nwith oral forms [ 96], which could provide better control \n\n1575\nCannabis for Gynecological Conditions\nfor the sudden breakthrough pain that commonly occurs in \nendometriosis (so called ‘endo flares’). This study also sug-\ngested improvements in comorbid symptoms such as mood \nand gastrointestinal symptoms, common in those with endo-\nmetriosis [19], and had greater improvement for oral dosage \nforms compared with inhaled [95], suggesting that tailoring \nthe mode of administration to target specific symptoms is \nan important clinical consideration. During the COVID-19 \npandemic, an international cross-sectional survey found that \n51% of 1634 respondents with endometriosis used cannabis \nin the 3 months prior [97]. Respondents with legal access \nwere more likely to consume cannabis than those without \nand were also more likely to disclose their usage to health-\ncare professionals. In many of these studies, a deprescribing \nor ‘substitution effect’ is reported where uptake in cannabis \nusage results in a reduction in one or more pharmaceuti-\ncals [94]. From a cross-sectional study of 213 participants \nin New Zealand, illicit cannabis use for managing pain \nand to improve sleep was reported in 95% of respondents, \nwith over 80% (n  = 176/213) indicating that cannabis had \nreduced their normal pharmaceutical medication usage [98]. \nAlmost two-thirds (n = 128/213) of respondents completely \nstopped a medication, most commonly analgesics (66%, \nn = 85/128), with opioids (40%, n = 51/128) being the most \ncommon analgesic stopped, followed by NSAIDs at 17% \n(n = 21/128), antidepressants (16%, n = 20/128), and ben-\nzodiazepines (15%, n = 9/128) [98]. In a separate study from \nAustralia and New Zealand, 237 people with endometriosis \nreported substantial substitution effects utilizing predomi-\nnantly illicit cannabis [99], with a 50% or more reduction in \nusage being reported for those who currently or previously \nused opioid analgesia (66%, n = 121/183), non-opioid anal-\ngesia (63%, n  = 147/233), neuroleptics (61%, n = 37/60), \nand anxiolytic medications (47.9%, n = 46/96).\n6  Risks of Cannabis Usage\nCannabis use for gynecological pain, whether legal or illicit, \nis not without side effects or risks [100]. Factors such as \nearly age of initiation associated with mental ill health in \nvulnerable populations, dependence, and abuse potential \n(i.e., particularly THC-dominant cannabis) are important \nclinical considerations for clinicians to discuss with their \npatients before prescribing or recommending medicinal can-\nnabis [96, 100]. The most common side effects reported by \ncannabis consumers in general include dry mouth, anxiety, \nnausea, dizziness, drowsiness/fatigue, and cognitive effects \n[96]. These are similar to those reported by people using \ncannabis for gynecological pain; 84% of those using can -\nnabis for pelvic pain reported side effects, most commonly \ndry mouth, sleepiness, and feeling ‘high’ [92]. In those with \nendometriosis, just under a third (28%) of cannabis users \nreported side effects; 75% reported feelings of euphoria, \n72% increased appetite, 67% dry mouth, and 35% feelings \nof mild anxiety or paranoia with medically diagnosed can-\nnabis; hyperemesis syndrome was reported by only two \nrespondents (<1%) [97]. However, cessation due to these \nside effects is relatively low, with just under 23% of those \nwho reported cessation of cannabis indicated it was due to \nside effects [97].\nDeprescribing associated with cannabis substitution is \npromising. However, research suggests that people are not \ninforming their medical doctor of their use of illicit cannabis \nfor therapeutic purposes, citing concerns over legal reper -\ncussions (combined 31.3%), societal judgment (29.2%), the \ndoctor’s reaction (29.2%), or the doctor’s presumed unwill-\ningness to prescribe (10.4%). This is concerning as many \nof the medications that are being reduced or discontinued, \nsuch as opioids and benzodiazepines, have potential for sig-\nnificant withdrawal [101, 102] if not tapered off correctly \nunder medical supervision. Therefore, doctors who work \nwith patients with endometriosis or other forms of chronic \npelvic pain should be aware of the likelihood of potential \ncannabis usage, and try to encourage disclosure of usage, \nor at minimum, closely monitor usage of these medications \nover time.\n7  Barriers to Usage\nWhilst the distinct lack of randomized clinical trial data may \nbe a significant barrier to cannabis adoption for gynecological \npain conditions such as CPP and endometriosis, there may be \nmore pernicious obstacles. The deleterious impact of stigma \nis well described in the medicinal cannabis cohort, and whilst \nsome have proposed that stigma is diminishing due to normali-\nzation in certain localities, there is little evidence to suggest \nit has disappeared [103]. Recent data from the UK of 2319 \npatients utilizing cannabis-based medicines (CBMs) indicated \nthat participants were afraid of what the police or criminal \njustice system (57.1%), other government agencies (55.3%), \nand healthcare professionals (40.2%) might think about their \ntreatment choice, suggestive of a high prevalence of perceived \nstigma [104]. Qualitative research of people utilizing illicit \ncannabis for therapeutic purposes shows that stigmatization \nis related to, and perpetuated by, the ambiguous status of can-\nnabis (i.e., both a legal medicine and illegal drug) and the lack \nof knowledge about medical cannabis amongst police, medical \nprofessionals, and the general public [105]. Additional qualita-\ntive research exploring the barriers, drivers and perceptions \nof cannabis use for primary dysmenorrhea (PD) in Australian \nwomen [106] goes further, showing that the perceived dam-\nage to their professional and social standing if their cannabis \nuse became known was a serious concern, despite its legality \nfor medical purposes. Participants spoke about the clandestine \n\n1576 J. Sinclair et al.\nway they had to consume cannabis for their pain and symp-\ntoms, and that even the possibility of being perceived as irre-\nsponsible, simply by virtue of being a cannabis user, was a \nsignificant barrier to adoption [106]. Stigma not only impacts \npeople directly, but also indirectly in the bias and opinions \nof the healthcare professionals they interact with. Surveyed \npharmacists have highlighted the impact that stigma can have \non patients, with the lack of public awareness and inability \nto distinguish between medicinal and recreational cannabis \nidentified as key factors contributing to public stigma [107, \n108]. Furthermore, effective treatment with medicinal canna-\nbis may be compromised by negative attitudes, stigmatized \nperceptions, and subjective norms of nurses and physicians \n[109], highlighting that health education for both health pro-\nfessionals and the general public plays a crucial role in reduc-\ning the impact of stigma [110]. This is particularly detrimental \ngiven that women with CPP and associated conditions such as \nendometriosis already experience stigma and discrimination \n[111, 112].\nThe impact of such stigma permeates into government \nlaws and corporate policies, notably drug-driving laws \nand workplace drug testing policies [113, 114]. This is a \nsignificant challenge as cannabis is one or more of (a) a \nlegal medicine, (b) a recreational/adult-use drug, and (c) an \nillicit/illegal substance, depending on geographic location \nand legal jurisdiction. This is reflected in the haze of issues \nwith preexisting drug-driving laws and workplace policies. \nWhilst road safety risks associated with the medicinal use of \ncannabis appear to be similar or lower than other potentially \nimpairing prescription medications [90], including those \ncommonly used in endometriosis such as opioids, in coun-\ntries such as Australia, patients utilizing medicinal cannabis \nare still subject to drug-driving testing, which detects for \npresence of THC alone, not impairment. Such laws crimi-\nnalize the presence of THC in body fluids irrespective of \nimpairment and appears to be linked to the historical status \nof cannabis as a Schedule 9 substance with no recognized \nmedical value [90]. Research has shown, particularly in \nthose living in regional and remote locations, that facing \nsuch criminal prosecution for driving whilst using canna-\nbis legally as a medicine is a significant barrier to adoption \n[106], giving rise to the need for updated drug-driving laws. \nSimilarly, workers in high-risk industries such as defense, \nconstruction, railroad, transport, maritime, and mining oper-\nations are similarly disadvantaged as these occupations are \nusually subjected to workplace drug testing policies [49].\n8  Illicit versus Legal Medicinal Cannabis\nIllicit cannabis is unlikely to have any accurate indication of \nthe level of THC, and the lack of any quality control precludes \nconsistency, making consistent dosing for medical purposes \nnext to impossible. Medicinal cannabis undergoes rigorous \ntesting procedures including microbial limits, cannabinoid \nstandardization, detection of foreign matter, aflatoxins, ochra-\ntoxin A, pesticide and solvent residues. This ability to culti-\nvate and standardize cannabinoids and manufacture medicinal \ncannabis products to high quality standards with reproducible \nresults means that accurate dosing is now possible [115, 116]. \nUnfortunately, the very ability to manufacture to these high \nstandards is now contributing to a significant cost-to-patient \nburden, which can in turn drive people to illicit or recreational \nmarkets to source cannabis for therapeutic self-management. \nInternational survey data from this team (manuscript under \nsubmission) examining the use of cannabis for endometriosis \npain and associated symptoms has identified that in countries \nsuch as Canada and the US, that have both legal medical and \nrecreational/adult-use models, most survey respondents were \nutilizing recreational/adult-use cannabis for therapeutic self-\nadministration over that of medical doctor prescription. Policy \nmakers in countries with newly minted medical cannabis pro-\ngrams need to consider the impact to public health that initiat-\ning adult-use legalization may have on the medical cannabis \nsector and consider thoughtful approaches to ensuring a co-\nhabitation of both is possible.\n9  Conclusion\nA variety of evidence shows that cannabis usage, either \nillicit or legally prescribed, is relatively common amongst \nthose with chronic pelvic pain. Cannabis appears to reduce \npain and other symptoms of endometriosis such as gastro-\nintestinal issues, with corresponding reported reductions or \ncessation in medications commonly used to manage these \nsymptoms such as opioids. Cannabis inhabits an unusual \nposition in our modern pharmacopoeia, being both a legal \nmedicine, a legal recreational drug, and an illegal drug, \ndepending on jurisdiction. This has led to issues with driv -\ning, workplace laws, and stigmatization that limit its usage \nas a legal medication. Clinicians working with endometriosis \npatients should be aware of high levels of cannabis usage \namongst this population and monitor any reductions in regu-\nlar medication, especially in the case of opioids and benzo-\ndiazepines. While promising, the safety and effectiveness of \ncannabis for various gynecological pain conditions needs to \nbe tested in rigorous clinical trials.\nAcknowledgments Funding has been provided to JS in the form of a \nWestern Sydney University Post-Graduate Research Scholarship.\nDeclarations \nFunding Open Access funding enabled and organized by CAUL and \nits Member InstitutionS. JS PhD is supported by a Western Sydney \nUniversity Post-Graduate Research Scholarship; however, no specific \nfunding was provided for preparing this manuscript.\n\n1577\nCannabis for Gynecological Conditions\nCompeting Interests As a medical research institute, NICM Health \nResearch Institute (at Western Sydney University) receives research \ngrants and donations from foundations, universities, government agen-\ncies, and industry. Sponsors and donors provide united and tied fund-\ning for work to advance the vision and mission of the Institute. JS is \nemployed by Australian Natural Therapeutics Group, and formerly sat \non the scientific advisory board for BioCeuticals. JS is also a current \nmember of the scientific advisory board for United in Compassion \n(pro bono) and a board member of the Australian Medicinal Canna-\nbis Association (pro bono). JA reports grant funding from MRFF for \nmultiple endometriosis-related research grants; honoraria, member on \nAdvisory Boards with Hologic Australia and CSL Vifor (formerly Vifor \nPharma Pty. Ltd.); is a member of the Endometriosis Advisory Group \nto the Australian Government, Chairs the Expert Endometriosis Work-\ning Group for the Australian and New Zealand College of Obstetricians \nand Gynaecologists (RANZCOG), was the chair for the publication \nof the Diagnosis and Management of Endometriosis Clinical Guide -\nline in 2021; and is the Deputy Editor of the Journal of Minimally \nInvasive Gynecology and Associate Editor of the Australian and New \nZealand Journal of Obstetrics and Gynaecology. MA is an advisory \nboard member for Evolv Health, reports grant funding from MRFF for \nmultiple endometriosis-related research grants, is chair of Endome-\ntriosis Australia’s Clinical Advisory Committee, and is a member of \nthe Expert Endometriosis Working Group for the Australian and New \nZealand College of Obstetricians and Gynaecologists (RANZCOG). \nAP declares that they have no conflicts of interest that might be relevant \nto the contents of this manuscript.\nAuthor Contributions JS and MA wrote the main manuscript. JA and \nAP provided feedback to the main manuscript. All authors reviewed \nthe manuscript prior to submission.\nEthics Approval Not applicable.\nConsent (Participation & Publication) Not applicable.\nData Availability Data sharing not applicable to this article as no data-\nsets were generated or analyzed during the current study.\nCode Availability Not applicable.\nOpen Access This article is licensed under a Creative Commons Attri-\nbution-NonCommercial 4.0 International License, which permits any \nnon-commercial use, sharing, adaptation, distribution and reproduction \nin any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Com-\nmons licence, and indicate if changes were made. The images or other \nthird party material in this article are included in the article’s Creative \nCommons licence, unless indicated otherwise in a credit line to the \nmaterial. 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