A new route for pain relief?
The endocannabinoid system was discovered in the 1990s, making it a relatively new area of therapeutic potential. Despite this, researchers now recognise it as a key regulator of pain, inflammation, and immune responses, all of which are central to endometriosis.
In this article, we’re going to dive into a paradox:
⦾ Endocannabinoids are our body’s natural pain relieving chemicals. Women with endometriosis have ELEVATED levels - yet are still in excruciating pain.
⦾ On the other hand, plant-derived cannabinoids, like THC and CBD, interact with this same system, and are self-reported to be an effective pain relief strategy in those with endometriosis.
How is this possible? And why is there growing interest in targeting this system for endometriosis pain, and even the possible slowing of endometriosis lesion growth?!
Let’s explore the science.
What is the endocannabinoid system? (1, 2)
The endocannabinoid system is active in the brain, nervous system, reproductive tract, and even the gut. It's involved in mood, stress responses, inflammation, and notably pain modulation and perception, where it can induce pain relief. It’s made up of:
1. Cannabinoid Receptors
❖ The two main receptors are CB1 and CB2. They're key in pain perception, neural signalling and inflammation.
2. Endocannabinoids
Endocannabinoids are naturally produced by our body, and bind to cannabinoid receptors. They act like neurotransmitters, but send signals the “wrong” way in a process called retrograde signalling! This acts as a kind of volume control on neural communication, dampening excessive signalling, including pain signals. Clever, right?
Endocannabinoids can become dysregulated in the body, and contribute to disease processes, such as in migraine, fibromyalgia, IBS, and chronic pain conditions. And of course, endometriosis.
The Paradox: Endometriosis and Endocannabinoids Dysregulation (3, 4)
Despite the fact that endocannabinoids should provide pain relief, women with endometriosis have ELEVATED levels - yet are still in excruciating pain.
Specific correlations are found between endocannabinoid levels and endometriosis symptoms, and they’re completely contradictory:
- Elevated AEA correlated with more severe period pain
- Elevated PEA correlated more severe painful intercourse
- Increased 2-AG and AEA were associated with greater abdominal pain intensity.
These are all endocannabinoids - molecules whose elevated levels should theoretically be providing pain relief. So why isn't it working?
Well, the tissue of those with endometriosis is found to have LOWER cannabinoid receptors (specifically CB1), meaning the natural pain relief signal has nowhere to land.
The body tries to compensate by producing more endocannabinoids, but the receptors simply aren't there to respond.
It becomes a failing cycle: the body increases its own endocannabinoid production in response to pain → lower CB1 receptor expression prevents adequate pain relief → the body compensates by producing even more.
To add to this: In women without endometriosis, CB1 receptor expression naturally increases in the luteal phase in response to rising progesterone, offering natural pain relief when the uterine lining is inflamed before menstruation. In endometriosis, progesterone resistance often occurs, and the upregulation of CB1 receptors is prevented, contributing to more painful periods.
But Plant-derived Cannabinoids Might Help Endo Pain?! (5)
Around 1 in 10 with endometriosis report using plant-derived cannabinoids as a self-management strategy, whether medically prescribed or not. It’s used to curb the emotional and physical burden of endometriosis symptoms. Self-reported pain reduction is rated 7.6/10, and studies on its use for chronic pelvic pain show effectiveness exceeding the minimum clinically important difference in pain for those with endometriosis.
Plant-derived cannabinoids like THC and CBD seem to instead work for pain relief - because they act differently from the endocannabinoids our bodies produce naturally - and in endometriosis, those differences may actually work in their favour.
1. They target the right receptors that are upregulated in endometriosis
✘ Our body's own endocannabinoids primarily bind to CB1 receptors, but these are found to be downregulated in endometriosis, meaning the signal isn't getting through effectively.
✓ Plant-derived cannabinoids, on the other hand, show stronger activity at CB2 receptors, which are actually upregulated in endometriotic lesions. In other words, they may be better equipped to engage with the receptors that are most active in the disease.
2. They relieve pain from the control centre (our brain!)
✘ Our natural endocannabinoids struggle to cross the blood-brain barrier and are broken down by enzymes before they can reach central pain-processing circuits.
✓ Plant-derived cannabinoids cross this barrier more efficiently and are more resistant to enzymatic degradation, meaning they can act on the brain's pain centres in a way our endogenous system simply can't.
3. They work through multiple pathways
✓ Beyond cannabinoid receptors, plant-derived cannabinoids - particularly CBD - exert anti-inflammatory effects through other non-cannabinoid pathways.
However, endometriosis-associated pain is complex, and the use of plant-derived cannabinoids for this is only just starting to be explored. Randomised, controlled trials are the gold standard for use of a treatment, and though there are studies in progress, data is yet to be published confirming efficacy in those with endometriosis.
Could Cannabinoids Slow the Progression of Endometriosis Lesions?
Beyond pain relief, rodent studies activating cannabinoid receptors showed:
- THC inhibited lesion growth
- CBD reduced lesion diameter and volume
- Reductions in inflammatory cytokine levels, and antioxidant effects
Research has also been done in vitro (in a dish!) in human endometrial samples.
Cannabinoid agonists were shown to inhibit endometriotic cell proliferation and modulate apoptosis, essentially encouraging abnormal cells to die off.
Adding another layer to this picture, CB1 receptors have been identified on the nerve fibers that innervate endometriotic growths, suggesting the endocannabinoid system may play a direct role in the local environment of lesions themselves.
The findings on endometriosis lesion growth are early-stage, and it's important to note that rodent and in vitro studies don't always translate to humans. But the convergence of evidence - reduced lesion size, lower inflammation, and direct receptor presence in lesion tissue - makes this an exciting area of research that warrants further investigation.
The Bottom Line
The science is still catching up, but the direction is promising. We know the endocannabinoid system is dysregulated in endometriosis and maps to symptoms, and we know cannabinoid receptors are present in the tissues affected by the disease.
Early signals into the use of plant-derived cannabinoids for endometriosis-associated pain appear promising, but researchers are still untangling how exactly endocannabinoid system dysregulation contributes to symptoms, and how it can be best targeted.
Translating this information into safe, effective, evidence-based treatment for people with endometriosis requires the kind of robust human trials that are only just beginning.
References;
- Rezende, B.; Alencar, A.K.N.; de Bem, G.F.; Fontes-Dantas, F.L.; Montes, G.C. Endocannabinoid System: Chemical Characteristics and Biological Activity. Pharmaceuticals 2023, 16, 148. https://doi.org/10.3390/ph16020148
- Capodice, J. L., & Kaplan, S. A. (2021). The endocannabinoid system, cannabis, and cannabidiol: Implications in urology and men's health. Current urology, 15(2), 95–100. https://doi.org/10.1097/CU9.0000000000000023
- Sanchez, A.M., Cioffi, R., Viganò, P. et al. Elevated Systemic Levels of Endocannabinoids and Related Mediators Across the Menstrual Cycle in Women With Endometriosis. Reprod. Sci. 23, 1071–1079 (2016). https://doi.org/10.1177/1933719116630414
- Farooqi, T., Bhuyan, D. J., Low, M., Sinclair, J., Leonardi, M., & Armour, M. (2023). Cannabis and Endometriosis: The Roles of the Gut Microbiota and the Endocannabinoid System. Journal of clinical medicine, 12(22), 7071. https://doi.org/10.3390/jcm12227071
- Armour, M. and Sinclair, J. (2023), Cannabis for endometriosis-related pain and symptoms: It's high time that we see this as a legitimate treatment. Aust N Z J Obstet Gynaecol, 63: 118-120. https://doi.org/10.1111/ajo.13642