Clinical Studies

Related research, resources and articles relating to cannabinoids and sexual health

Woman Scientist Looking Through Microscope

Why Cannabis?

The endocannabinoid system (ECS) has been implicated in the pathophysiology of endometriosis progression and related pain. The ECS is a vital system consisting of receptors (CB1, CB2), enzymes and ligands which regulate physiological processes.

CB1 receptors, normally abundant in the uterus, are reduced in patients with endometriosis, contributing to inflammation and pain.1

Utilizing THC and CBD, which activate these receptors, may help correct deficiencies in the underlying endocannabinoid tone.2 Suppositories provide a local effect that can reduce nociceptive, inflammatory, and neurogenic pain while reducing unwanted systemic side effects.

1  Bouaziz, J., Bar On, A., Seidman, D. S., & Soriano, D. (2017). The Clinical Significance of Endocannabinoids in Endometriosis Pain Management. Cannabis and Cannabinoid Research, 2(1), 72–80.doi:10.1089/can.2016.0035

2  Dmitrieva, N., Nagabukuro, H., Resuehr, D., Zhang, G., McAllister, S. L., McGinty, K. A., … Berkley, K. J. (2010). Endocannabinoid involvement in endometriosis. Pain, 151(3), 703–710. doi:10.1016/j.pain.2010.08.037


Cannabinoids in Gynecological Diseases

The endocannabinoid system (ECS) is a multifunctional ho­meostatic system involved in many physiological and patho­logical conditions. The ligands of the ECS are the endo­cannabinoids, whose actions are mimicked by exogenous cannabinoids, such as phytocannabinoids and synthetic cannabinoids. Responses to the ligands of the ECS are medi­ated by numerous receptors like the classical cannabinoid receptors (CB1 and CB2) as well as ECS­related receptors, e.g., G protein­coupled receptors 18 and 55 (GPR18 and GPR55), transient receptor potential ion channels, and nuclear per­oxisome proliferator­activated receptors. The ECS regulates almost all levels of female reproduction, starting with oocyte production through to parturition. Dysregulation of the ECS is associated with the development of gynecological disor­ders from fertility disorders to cancer. Cannabinoids that act at the ECS as specific agonists or antagonists may potential­ly influence dysregulation and, therefore, represent new therapeutic options for the therapy of gynecological disor­ders.


Pharmacokinetics and Tolerability of Δ9-THC-Hemisuccinate in a Suppository Formulation as an Alternative to Capsules for the Systemic Delivery of Δ9-THC

<p class=”p2″><span class=”s1″><span class=”Apple-converted-space”> </span></span>The objectives of this study were: (1) to assess the safety, tolerability, and pharmacokinetics of ascending doses of Δ<span class=”s2″>9</span>- tetrahydrocannabinol-hemisuccinate (THC-HS) after rectal administration as suppositories in male volunteers; and (2) to compare the pharmacokinetics of oral administration of Δ<span class=”s2″>9</span>-tetrahydrocannabinol (Δ<span class=”s2″>9</span>-THC) with an equivalent amount of Δ<span class=”s2″>9</span>-THC delivered as THC-HS via the suppository formulation. In support of the pharmacokinetic evaluations, an analytical method was developed and validated for the determination of Δ<span class=”s2″>9</span>-THC and for its major circulating metabolites 11-hydroxy-Δ<span class=”s2″>9</span>-tetrahydrocannabinol (11-OH-THC) and 11-nor-Δ<span class=”s2″>9</span>-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) in human plasma. Δ<span class=”s2″>9</span>-THC, 11-OH-THC, and THC-COOH were extracted from plasma using solid phase extraction and analyzed by liquid chromatography-tandem mass spectrometry. The limits of detection and quantitation for all 3 analytes were 0.25 and 0.5 ng/mL, respectively. The method was validated over the range of 0.5–25 ng/mL. This method was used to quantify Δ<span class=”s2″>9</span>-THC and any THC-HS as Δ<span class=”s2″>9</span>- THC due to the inclusion of a hydrolysis step as part of the extraction procedure. Therefore, Δ<span class=”s2″>9</span>-THC measured was the total THC (free Δ<span class=”s2″>9</span>-THC plus Δ<span class=”s2″>9</span>-THC derived from THC-HS). The assay was reproducible for the measurement of all 3 analytes, with a variability of 7.2, 13.7, and 8.3%, respectively, at the 1 ng/mL level. The method was then used to assess the pharmacokinetics of Δ<span class=”s2″>9</span>-THC and metabolites from the suppository dosage form in doses equivalent to 1.25, 2.5, 5, 10, and 20 mg Δ<span class=”s2″>9</span>-THC per suppository as THC-HS. Systemic exposure to Δ<span class=”s2″>9</span>-THC, administered as THC-HS suppository, increased broadly dose proportionally. Systemic exposure and C<span class=”s2″>max (obs) </span>estimates for 11-OH-THC and THC-COOH generally increased subproportionally. The pharmacokinetic profiles of Δ<span class=”s2″>9</span>-THC and metabolites were also compared after oral administration of 10 mg Δ<span class=”s2″>9</span>-THC (as dronabinol capsules) and after administration of 10 mg equivalents of Δ<span class=”s2″>9</span>-THC as THC-HS in suppository form. Total systemic exposure to Δ<span class=”s2″>9</span>-THC was considerably higher following rectal administration of THC-HS than after oral administration. The Δ<span class=”s2″>9</span>-THC area under the plasma concentration versus time curve (AUC<span class=”s2″>(0–∞)</span>) for THC-HS was 2.44-fold higher (90% confidence interval: 1.78, 3.35) than for the capsule administration.<span class=”Apple-converted-space”> </span></p>
<a href=”Δ9-THC-Hemisuccinate-in-a-Suppository-Formulation-as-an-Alternative-to-Capsules-for-the-Systemic-Delivery-of-Δ9-THC.pdf” target=”_blank” rel=”noopener”>VIEW/DOWNLOAD REPORT</a>


The use of cannabis for symptoms of endometriosis was investigated utilising retrospective archival data from Strainprint Technologies Ltd., a Canadian data technology company with a mobile phone application that tracks a range of data including dose, mode of administration, chemovar and their effects on various self-reported outcomes, including pelvic pain.


Disease-modifying effects of natural D9-tetrahydrocannabinol in endometriosis-associated pain

Endometriosis is a chronic painful disease highly prevalent in women that is defined by growth of endometrial tissue outside the uterine cavity and lacks adequate treatment. Medical use of cannabis derivatives is a current hot topic and it is unknown whether phytocannabinoids may modify endometriosis symptoms and development. Here we evaluate the effects of repeated exposure toD9-tetrahydrocannabinol (THC) in a mouse model of surgically-induced endometriosis. In this model, female mice develop mechanical hypersensitivity in the caudal abdomen, mild anxiety-like behavior and substantial memory deficits associated with the presence of extrauterine endometrial cysts. Interestingly, daily treatments with THC (2 mg/kg) alleviate mechanical hypersensitivity and pain unpleasantness, modify uterine innervation and restore cognitive function without altering the anxiogenic phenotype. Strikingly, THC also inhibits the development of endometrial cysts. These data highlight the interest of scheduled clinical trials designed to investigate possible benefits of THC for women with endometriosis.


Endocannabinoids modulate apoptosis in endometriosis and adenomyosis
Adenomyosis that is a form of endometriosis is the growth of ectopic endometrial tissue within the muscular wall of the uterus (myometrium), which may cause dysmenorrhea and infertility. Endocannabinoid mediated apoptotic mechanisms of endometriosis and adenomyosis are not known. We hypothesized that the downregulation of endocannabinoid receptors and/or alteration in their regulatory enzymes may have a direct rolein the pathogenesis of endometriosis and adenomyosis through apoptosis. Endocannabinoid receptors CB1 andCB2, their synthesizing and catabolizing enzymes (FAAH, NAPE-PLD, DAGL, MAGL) and the apoptotic indexes were immunohistochemically assessed in endometriotic and adenomyotic tissues. Findings were compared to normal endometrium and myometrium. Endometrial adenocarcinoma (Ishikawa) and ovarian endometriosis cyst wall stromal (CRL-7566) cell lines were furthermore cultured with or without cannabinoid receptor agonists. The IC50 value for CB1 and CB2 receptor agonists was quantified. Cannabinoid agonists on cell death were investigated by Annexin-V/Propidium iodide labeling with flow cytometry. CB1 and CB2 receptor levels decreased in endometriotic and adenomyotic tissues compared to the control group (p = 0,001 and p = 0,001). FAAH, NAPE-PLD, MAGL and DAGL enzyme levels decreased in endometriotic and adenomyotic tissues compared to control (p = 0,001, p = 0,001, p = 0,001 and p = 0,002 respectively). Apoptotic cell indexes both in endometriotic and adenomyotic tissues also decreased significantly, compared to the control group (p = 0,001 and p = 0,001). CB1 and CB2 receptor agonist-mediated dose-dependent fast anti-proliferative and pro-apoptotic effects were detected in Ishikawa and ovarian endometriosis cyst wall stromal cell lines (CRL-7566). Endocannabinoids are suggested to increase apoptosis mechanisms in endometriosis and adenomyosis. CB1 and CB2 antagonists can be considered as potential medical therapeutic agents for endometriosis and adenomyosis. VIEW/DOWNLOAD REPORT
Antiproliferative Effects of Cannabinoid Agonists onDeep Infiltrating Endometriosis
Deep infiltrating endometriosis (DIE) is characterized by chronic pain, hyperproliferation of endometriotic cells and fibrosis. Since cannabinoids are endowed with antiproliferative and antifibrotic properties, in addition to their psychogenic and analgesic effects, cannabinoid agonists have been evaluated in DIE both in Vitro and in vivo. The in-vitro effects of the cannabinoid agonist WIN 55212-2 were evaluated on primary endometriotic and endometrial stromal and epithelial cell lines extracted from patients with or without DIE. Cell proliferation was determined by thymidine incorporation and production of reactive oxygen species by spectrofluorometry. ERK and Akt pathways were studied by immunoblotting. Immuno-blotting of-smooth muscle actin was studied as evidence of myofibroblastic transformation. The in vivo effects of WIN 55212-2 were evaluated on Nude mice implanted with human deep infiltrating endometriotic nodules. The in vitro treatment of stromal endometriotic cells by WIN 55212-2 decreased cell proliferation, reactive oxygen species production, and-smooth muscle actin expression. The decrease in cell proliferation induced by WIN 55212-2 was not associated with a decrease in ERK activation but was associated with the inhibition of Akt activation. WIN55212-2 abrogated the growth of endometriotic tissue implanted in Nude mice. Cannabinoid agonists exert anti-proliferative effects on stromal endometriotic cells linked to the inhibition of the Akt pathway. These beneficial effects of cannabinoid agonists on DIE have been confirmed in vivo.(Am J Pathol 2010,177:2963–2970; DOI: 10.2353/ajpath.2010.100375) VIEW/DOWNLOAD REPORT
The role of the endocannabinoid system in aetiopathogenesis of endometriosis: A potential therapeutic target

Endometriosis affects a large proportion of women during their reproductive years and is associated with pain and infertility, also affecting psychological wellbeing and quality of life. The pathogenesis of the disease remains unclear, although it is believed to be multifactorial. The endocannabinoid system (ECS) consists of a number of ligands, receptors and enzymes, and has gained interests in endometriosis research. This review aims to summarise all available evidence reporting the roles of the ECS in endometriosis. A literature search of the PubMed, EMBASE, and Web of Science electronic medical databases was performed. Original and review articles published in peer-reviewed journals were included. No publication date or publication status restrictions were imposed. Significant differences in the concentrations and expressions of the components of the ECS were reported in the eutopic and ectopic endometrium, and the systemic circulation of women with endometriosis compared to controls. Endometriosis appears to be associated with downregulation of CB1 receptors and upregulation of TRPV1 receptors. The role of CB1 and progesterone in anti-inflammatory action and the role of TRPV1 in inflammation and pain are of particular interests. Furthermore, the ECS has been reported to be involved in processes relevant to endometriosis, including cell migration, cell proliferation, apoptosis, inflammation, and interacts with sex steroid hormones. The ECS may play a role in disease establishment, progression, and pain in endometriosis. However, reports are based on studies of limited size and there are inconsistencies among the definition of their control groups. There are also conflicting reports regarding precise involvement of the ECS in endometriosis. Future research with larger numbers, strict inclusion and exclusion criteria and detailed clinical information is imperative.


The clinical significance of endocannabinoids in endometriosis pain management

Patients with endometriosis often suffer from diffuse and poorly localized sever pain. The current pain management strategies include medical and hormonal therapy, as well as surgery. Medical management of pain is often insufficient and is associated with high rate of recurrence. This review describes the multiple and complex pain mechanisms associated with endometriosis.


Endocannabinoid involvement in endometriosis
Endometriosis is a disease common in women that is defined by abnormal extrauteral growths of uterine endometrial tissue and associated with severe pain. Partly because how the abnormal growths become associated with pain is poorly understood, the pain is difficult to alleviate without resorting to hormones or surgery, which often produce intolerable side effects or fail to help. Recent studies in a rat model and women showed that sensory and sympathetic nerve fibers sprout branches to innervate the abnormal growths. This situation, together with knowledge that the endocannabinoid system is involved in uterine function and dysfunction and that exogenous cannabinoids were once used to alleviate endometriosis associated pain, suggests that the endocannabinoid system is involved in both endometriosis and its associated pain. VIEW/DOWNLOAD REPORT


Tetrahydrocannabinol Reduces Hapten-Driven Mast Cell Accumulation and Persistent Tactile Sensitivity in Mouse Model of Allergen-Provoked Localized Vulvodynia

Vulvodynia is a remarkably prevalent chronic pain condition of unknown etiology. An increase in numbers of vulvar mast cells often accompanies a clinical diagnosis of vulvodynia and a history of allergies amplifies the risk of developing this condition. We previously showed that repeated exposures to oxazolone dissolved in ethanol on the labiar skin of mice led to persistent genital sensitivity to pressure and a sustained increase in labiar mast cells. Here we sensitized female mice to the hapten dinitrofluorobenzene (DNFB) dissolved in saline on their flanks, and subsequently challenged them with the same hapten or saline vehicle alone for ten consecutive days either on labiar skin or in the vaginal canal. We evaluated tactile ano-genital sensitivity, and tissue inflammation at serial timepoints. DNFB-challenged mice developed significant, persistent tactile sensitivity. Allergic sites showed mast cell accumulation, infiltration of resident memory CD8+CD103+ T cells, early, localized increases in eosinophils and neutrophils, and sustained elevation of serum Immunoglobulin E (IgE). Therapeutic intra-vaginal administration of D9-tetrahydrocannabinol (THC) reduced mast cell accumulation and tactile sensitivity. Mast cell-targeted therapeutic strategies may therefore provide new ways to manage and treat vulvar pain potentially instigated by repeated allergenic exposures.


Cannabis and Vulvodynia Symptoms: A Preliminary Report

Medical marijuana has a long history of use as an analgesic for chronic pain disorders, including
dyspareunia (pain during intercourse), a hallmark of the rare chronic pain disorder vulvodynia.
Many women’s health topics remain under investigated. Few studies address cannabis’s potential
to treat vulvodynia symptoms despite their dramatic impact on quality of life. Women who had
used cannabis and who reported experiencing vulvodynia symptoms (N = 38) completed an online
survey assessing symptoms, expectancies regarding cannabis-associated relief from vulvodynia
symptoms, cannabis use, and cannabis-related problems. Generally, women expected cannabis to
have moderate to large effects on vulvodynia symptoms (d = .63-1.19). Nevertheless, women
expected greater relief for burning/stabbing pain than for itching and pain associated with tampon
insertion, as well greater relief for dyspareunia than for pain associated with tampon insertion.
Those whose symptoms were worse expected more relief from cannabis treatment. Expectations
of cannabis-induced relief did not increase frequency of use or problems. These data support the
idea that further work is warranted, including placebo-controlled randomized clinical trials to rule
out any placebo effects and identify potential adverse side effects from a cannabis treatment for


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