The therapeutic potential of cannabis in endometriosis

Endometriosis affects about one in ten women of reproductive age, causing pain, infertility and gastrointestinal symptoms. Treatment options include surgery or hormone therapy, but these are not always effective and often have significant adverse effects. Currently, there is growing evidence that not only proves the benefits of cannabinoid treatment but also the role of the Endocannabinoid System in controlling the progression of this pathology and in maintaining women's health.

What is Endometriosis?

The endometrium is one of the layers that make up the uterus and corresponds to its inner lining. During the menstrual cycle, it is cyclically regenerated through a peeling process, which corresponds to menstruation, and allows the renewal of all the elements of its tissue. Endometriosis is the name given to the clinical process in which the cells that make up the endometrium are located outside their normal location, for example in the pelvic peritoneum, ovaries, bladder, appendix, intestines or even the diaphragm.

In addition to these forms, which manifest in the abdominal cavity, endometriosis can, although more rarely, affect more distant organs, such as the lung, nose or skin.

About 1 in 10 women in the world suffers from endometriosis [1], corresponding to about 200 million women affected by this pathology worldwide. About 10% occurs in women of reproductive age, with the prevalence increasing to about 25% to 45% in infertile women. Diagnosis is late and the cause of endometriosis is currently unknown.

Symptoms

The main symptoms include pain and discomfort resulting from the associated inflammation, dyspareunia (pain associated with sexual intercourse), intestinal and urinary disorders and neuropathy (weakness, numbness and pain caused by nerve damage) of the lower extremities. Endometriosis is also the leading cause of infertility, early hysterectomies, stress and loss of ability to work. [2][3][4].

Endometriosis pain is very disabling and has a strong impact on many aspects of a woman's life. Its form of presentation is very variable and depends on the severity of the disease and the location of the endometriosis foci. This pain can arise associated with menstruation and initially gives in to treatment with anti-inflammatory drugs or the pill. As it becomes more intense, it stops responding to treatment.

Depending on its location, the pain is different: it can occur in the pelvic region or it can appear in the form of intestinal cramps, especially during menstruation, associated with diarrhea or, more rarely, constipation. If it affects the bladder, pain occurs during urination, and blood loss in the urine (hematuria) may occur. Rectal hemorrhages (rectal bleeding) occur when endometriosis invades the rectal mucosa. If it is present in the ureters, irreversible failure of kidney function can occur. Many women also report heavy menstruation.

It is important to note that, when not diagnosed and treated, endometriosis tends to progress, invading other tissues. On the other hand, there seems to be a correlation between this pathology and clear cell carcinoma of the ovary, which reinforces the need for early diagnosis and treatment. Infertility is another of its manifestations and results from the invasion and occlusion of the fallopian tubes by the endometrial tissue.

Treatment

There is no cure for endometriosis, so treatment should be aimed at relieving pain and other symptoms, increasing the chances of pregnancy and reducing its outbreaks.

Surgical treatment consists of removing the foci by laparoscopy. Whenever possible, we try to eliminate only these points. If this is not feasible, as is the case with more extensive forms, surgery will involve excision of the affected pelvic organs.

With regard to medical treatment, it consists of pain control, through the use of analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) or hormonal therapy. This type of approach has side effects and can decrease quality of life.

The control of hyperalgesia in patients with endometriosis is currently a medical challenge. The strategies used focus essentially on the use of analgesics, anti-inflammatory drugs, hormone therapy and/or surgical resection, and this type of approach causes adverse effects, as well as a decrease in quality of life. This approach is associated with a high relapse rate and provides only partial relief of symptoms. [4] [5] [6] [7]

The pain and psychological effects associated with endometriosis

Pain mechanisms associated with endometriosis are complex and interconnected and can be divided into three main categories of pain: nociceptive, inflammatory and neuropathic.

Photo: DR Journal of Molecular Endocrinology 50, 1; 10.1530/JME-12-0182

Pain perception is different from patient to patient, varying in intensity according to psychological, cultural and personal factors. [8] When we refer to the pain caused by endometriosis, it can have a great psychological impact on a woman's life, due to the nature of the disease and the limitations it causes at the reproductive level, especially dyspareunia and fertility issues [9] ]. Both factors can increase anxiety levels and translate into an exacerbated negative response in anticipation of pain, which, in turn, amplifies the painful experience. [10] These symptoms are believed to have a major impact on self-esteem and interpersonal relationships. [11]

Endometriosis and the Endocannabinoid System

Recently, the way in which the Endocannabinoid System (ESA) interacts with specific mechanisms associated with the establishment of pain, such as inflammation, cell proliferation and survival, has been demonstrated. [12] [13] [14] [15] [16] [17] [18] [19] These mechanisms play a key role in endometriosis-associated pain.

ECS is defined as a group of endogenous cannabinoid receptors, neurotransmitters and enzymes necessary for the biosynthesis and degradation of neurotransmitters, which are predominantly located in the brain, central nervous system (CNS) and peripheral nervous system (PNS). [20] [21]. The SEC is involved in many physiological processes, including pain sensation, appetite, mood and memory, and in mediating the psychoactive effects of cannabis.

CB1 receptors are highly expressed in the uterus (this being the site of the human body with the highest density of cannabinoid receptors besides the brain), as well as in various non-reproductive tissues. [22] CB2 receptors are abundantly expressed in the immune system, intestines, and other tissues such as the lungs, uterus, pancreas, and skin. [12] Studies demonstrate that human oocytes express CB1 and CB2 receptors and their location varies during the stages of oocyte maturation. [23] In addition, the presence of anandamide (AEA) has been demonstrated in the fluids of the female reproductive tract as well as in the ovaries. [24] AEA plays an important role in folliculogenesis, pre-ovulatory follicle maturation, oocyte maturation and ovulation. [25] A study of women undergoing fertilization vitro revealed that there are higher levels of AEA in plasma during ovulation and significantly lower levels during implantation, which are of high importance for successful pregnancy. [26] Furthermore, alterations in endocannabinoid signaling promote miscarriage in early pregnancy [27] which reveals the pivotal role of ECS in female reproduction.

Similar to cancer, endometrial cells do not undergo apoptosis and migrate to other parts of the body. Under ideal conditions, the endocannabinoid system, responsible for keeping our body in balance, promotes apoptosis of this type of cells, preventing their proliferation. Ethan Russo was the first scientist to describe that a deficit in endocannabinoid tone leads to the development of certain pathologies. Russo suggests that the lack of control in the multiplication of endometrial tissue cells and their consequent migration is due to a dysfunction of the cannabinoid receptors (CB1 and CB2). [28]

Cannabidiol (CBD), by activating transient vanilloid potential receptors subtype I (TRPV1), causes their desensitization, attenuating the sensation of pain. In addition, cannabidiol acts via the GPR18 receptor. This last receptor is activated by several endogenous lipids and its stimulation potentiates cell migration. It is known that GPR18 is activated by N-arachidonylglycine (NAGly), a component formed from the degradation of anandamide by the enzyme FAAH. Cannabidiol inhibits the formation of FAAH, thereby decreasing the metabolism of anandamide to NAGly (GPR18 stimulant) and other metabolites. In addition, CBD has already been shown to be an antagonist of GPR18, which reveals its importance in preventing the abnormal spread of endometrial tissue. [29]

Clinical Trials

Δ9-tetrahydrocannabinol (THC) is one of the psychoactive constituents of the plant Cannabis sativa and several clinical animal studies suggest its efficacy in relieving chronic pain [30] [31] [32] [33] [34] [35] through the activation of G protein-coupled cannabinoid receptors (CB1 and CB2).

In 2020 a clinical trial was carried out in mice with endometriosis. The administration of 2mg/kg of THC for 32 days led to the evident inhibition of the development of endometrial cysts. The anxiolytic effect was observed with lower THC doses (0,3 mg/kg), evidencing the biphasic effect of phytocannabinoids. The data obtained in this preclinical study emphasize the interest of clinical investigation in order to evaluate the effects of moderate doses of THC in patients with endometriosis. [36]

Sanchez et al. performed a study [13] in which the authors compared the plasma levels of endocannabinoids [AEA, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)) in women with pain associated with endometriosis. This study revealed a significant increase in these neurotransmitters and a decrease in CB1 expression. This result suggests a regulation of the negative feedback loop, which may impair the ability of these mediators to control pain in patients with endometriosis. The most common symptoms of pain associated with endometriosis are chronic pelvic pain, dysmenorrhea and dyspareunia, so the authors measured levels of these endocannabinoids in women who had any of these symptoms. From this evaluation, they concluded that women with dysmenorrhea (moderate to severe) have high levels of AEA and women with dyspareunia (moderate to severe) have higher levels of PEA. The result of this study suggests that ECS dysregulation may be implicated in the progression of symptoms associated with endometriosis.

In 2017, in Australia, an online questionnaire was carried out to women between the ages of 18 and 45 with a surgically confirmed diagnosis of endometriosis. Several questions were asked, such as the type of treatment they used, changes in symptoms, use of other medications, treatment costs and adverse effects. They analyzed about 484 responses where 76% of the women reported using cannabinoid therapy. The effectiveness in terms of reducing pain in the group that used cannabinoid therapy was high, with about 56% reducing the consumption of other drugs by less than half. Improvements in sleep quality, nausea and vomiting were also reported. [37]

Sinclair, J., Smith, CA, Abbott, J., Chalmers, KJ, Pate, DW, & Armour, M. (2019). Cannabis Use, a Self-Management Strategy Among Australian Women With Endometriosis: Results From a National Online Survey. Journal of Obstetrics and Gynecology Canada. doi:10.1016/j.jogc.2019.08.033

To date, no clinical trial has been conducted to assess the therapeutic potential of cannabis in women with endometriosis.

The closest example was a randomized, placebo-controlled clinical trial [38] where the efficacy of PEA), an endogenous lipid signaling molecule (similar to anandamide), administered concomitantly with transpolidatin (a natural precursor of resveratrol), for the treatment of chronic pelvic pain associated with endometriosis.

The mechanism of action of PEA was first described in 1957 by Nobel laureate and Professor Rita Levi-Montalcini [39]. PEA is considered an SEC modulator since it potentiates the effect entourage, reducing the enzymatic degradation of anandamide and increasing its affinity for its receptors.

''The Clinical Significance of Endocannabinoids in Endometriosis Pain Management”

In this study, treatment with PEA/transpolidatin proved to be promising, proving to be more effective than placebo in controlling colic, dyspareunia and pelvic pain in general. However, it was not as effective as the NSAID's used in this same trial.

The results are encouraging regarding improvement in pelvic pain, as all clinical studies showed statistically significant improvement in dysmenorrhea and CPP. The randomized control study conducted by Cobellis et al., [38] showed better results than placebo, but a less significant decrease in symptoms than with the use of NSAIDs. The use of NSAIDs, however, seems to have more side effects with long-term use and more contraindications.

Studies looking at “women's sex life” or “dyspareunia” [19] [39][40] showed significant improvement with the use of PEA. Another notable point is that none of these studies reported adverse side effects.

Two clinical trials with phytocannabinoids are currently underway:

– an open-label, phase II study taking place at the Hospital Clinic in Barcelona, ​​where the efficacy of administering THC and CBD 1:1 to patients with hyperalgesia due to endometriosis will be evaluated. [41]

– A Phase III, double-blind, randomized, placebo-controlled study, taking place at Milton S. Hershey Medical Center, where the efficacy of adjunctive treatment of CBD (10-20mg) with hormone therapy (Norethindrone acetate) in the control of endometriosis-derived pain. [42]

Conclusion

Endometriosis is associated with a deficiency of SEC, partly explaining the exacerbation of pain due to low levels of CB1 receptors in endometrial tissue. The modulation of the SEC is presented as a good therapeutic strategy, as it directs CB1 receptors expressed at the peripheral level, thus controlling pain, regulation of the hormonal and immune system, decreased proliferation, increased apoptosis and normalization of invasive mechanisms and mechanisms of neoangiogenesis.

With the data presented, it is also concluded that phytocannabinoids are an effective tool in relieving pain and improving the quality of life of women with endometriosis. In order for cannabinoid-based treatment to be carried out in a safe and effective way, follow-up by a health professional is necessary.

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[41] Clinical Trial – Effect of Cannabinoid (THC / CBD 50%) on Hyperalgesia in Patients With Deep Endometriosis (EdomTHC)

[42] Clinical Trial – “Cannabidiol and Management of Endometriosis Pain” 

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* Soraia Tomás é Nurse, graduated from the Nursing School of Coimbra in 2015. Worked in intensive care of Cardio-Thoracic surgery and lung transplantation in Lisbon. She currently works at the Spine Center, a spine surgery service and an intensive care unit for general surgery at Hospital da Luz in Coimbra, the city where she lives. Enthusiastic in the field of Medicinal Cannabis, he is a member of the scientific council of the Portuguese Observatory of Medicinal Cannabis, attended conferences in this area (Portugal Medical Cannabis, Cannabis Europa, CannX, among others) and obtained a postgraduate degree in GMP's for Medicinal Cannabis, course carried out by the Portuguese Observatory of Medicinal Cannabis in partnership with the Military Laboratory of Chemical and Pharmaceutical Products and the Faculty of Pharmacy of the University of Lisbon. President of the Board of APCNNA – Portuguese Association for Information on Cannabis, intends to develop projects dedicated to the dissemination, education and training in medical cannabis to health professionals and the general public, thus promoting excellence in professional practice and safe and effective access. to cannabinoid therapies.