The Endocannabinoid System and Estrogen
The trend towards the legalization of marijuana and the increasing use of this herbal product and its oils (CBD) for both recreational and therapeutic uses begs a question: What impact does it have on sex hormones and reproductive functions, as well as on other critical health issues, such as cognition and immune health? Cannabis sativa has long been a widely consumed plant recognized for its psychoactive properties and its reported impact on multiple functions, including metabolism, sexual functioning, and motivation. In the 1960’s tetrahydrocannabinol (THC) was identified as the primary active component of cannabis, but the site of action was not known until the discovery of the cannabinoid receptor.
The endocannabinoid system is a key physiological system, involved in the foundation of health maintenance. The receptors are found in the brain, in numerous organs, connective tissue, glands, and in immune cells. It has complex actions on the immune system, the nervous system, and in all the organs within the body, and can be viewed as a powerful connection between the body and the mind. The endocannabinoid system literally links the state of physicality and disease to brain functioning. The endocannabinoid system, whether through naturally made endocannabinoids or marijuana and its derivatives, or similar plant-derived cannabis, impacts humans in ways that are immensely complex and challenging.
Marijuana is commonly used and its use by women is rising. Women have been found to be more susceptible to abuse of cannabinoids and the development of dependence, and experience more severe withdrawal symptoms and relapse more often than do men. As well, when women use cannabinoids, they are more impacted, with altered functioning on tasks. In adolescents, females are more likely to be adversely affected than are male adolescents by cannabinoids. Importantly, it is now accepted that estradiol is the hormone that impacts this important sexual dimorphic effect of cannabinoids.
The cannabinoid receptors are now recognized as constituents of a neuro-modulatory system named the endocannabinoid system, which is located throughout the central nervous system and peripherally and is involved in the regulation of many bodily functions as well as behaviors. It is now understood that the gonadal hormones are equally involved in a myriad of physiological functions and behaviors and it has been found that the two systems are intimately interconnected. There are endocannabinoid components present throughout the hypothalamus-pituitary-gonadal axis (HPG axis) and the potential for there to be damage to its proper functioning exists if the endocannabinoid system is tampered with.
Research is revealing that there exists a bidirectional relationship between the endocannabinoid system and gonadal hormones. If changes to the HPG axis occur, there can be an impact on the functioning of the endocannabinoid system. And the endocannabinoid system is involved in many functions, as mentioned, including sexual behavior, which are of course regulated by gonadal hormones. Clearly there is a complex, bidirectional interaction between the two systems.
It is know recognized that the endocannabinoid system contains two types of cannabinoid receptors: CB1 and CB2 receptors. The ligands for these receptors are anandamide and 2-arachidonoylglycerol (2-AG). The CB1 receptors are in the central nervous system and in some peripheral sites. Within the CNS, they are primarily located within the neurons of the cerebral cortex, hippocampus, amygdala, hypothalamus, basal ganglia, and cerebellum. The CB2 receptors are predominantly found in peripheral tissues and in cells of the immune system.
The CB1 receptors are in the presynaptic neurons on the axon terminals. The endocannabinoids themselves are synthesized and released on demand by the postsynaptic neurons. When the receptors are bonded with the ligand endocannabinoids, the release of additional neurotransmitters by the presynaptic cell is blocked, thereby allowing regulation of neurotransmission of incoming signals. FAAH, fatty acid amide hydrolase, is an enzyme which breakdowns anandamide and monoacylglycerol lipase breakdowns 2- AG, controlling quantities. FAAH is under the control of estradiol.
The endocannabinoid system and estrogens have both direct and indirect interactions. The endocannabinoid system impacts the release of estrogens through the central down-regulation of LH and GnRH. When THC is given, there is a decrease in serum LH, and the pulsatile nature of LH is decreased. When GnRH was given to female rats, the effects of THC were reversed. This is suggestive that as the pituitary gland remains sensitive to stimulation, the impact of cannabinoids is through its effects on central neurotransmission, suppressing LH release. The suppression of LH release by THC has been demonstrated in monkeys and rats. It is complex and variable by brain region and even by synapses, but changes to the function of estrogen do influence central endocannabinoid signaling. There is clearly a complex interrelationship between endocannabinoid activity and estradiol levels. It certainly appears that the use of an exogenous cannabinoid could adversely impact the hormonal cycling and fertility of females.
Here is a summary of what is currently known about the interrelationship of endocannabinoids and estrogen. Central CB1 receptor expression is modulated by estradiol and estradiol also increases anandamide synthesis while decreasing FAAH activity. FAAH is the principle enzyme which degrades the endocannabinoid anandamide. Reductions in this degrading enzyme would, of course, increase the amount of the cannabinoid present. The higher amount of the endocannabinoid present then decreases GnRH release, and this results in less FSH and LH release. The consequence of these gonadotropin decreases is a decrease in the release of estrogen from the ovaries. Estradiol also down-regulates FAAH activity peripherally in both the uterus and in immune cells.
Endocannabinoid activity as well as CB1 receptor function fluctuates throughout the menstrual cycle. In humans, the amount of anandamide circulating is higher during the follicular phase and highest during ovulation, while being lower during the luteal phase. It appears that the endocannabinoid system is significant in the regulation of the menstrual cycle and indeed does play a role in fertility. Various components of the endocannabinoid system have been found in the ovaries and uterus, and levels vary in a set manner during the time of embryo implantation. Data suggests that low anandamide levels are a requirement for implantation and for carrying a pregnancy to term, while high levels of anandamide facilitates the labor process. In fact, it has been found that during pregnancy there are low levels of anandamide present and a surge occurs near the time of labor onset. As well, with increased levels of anandamide or if an agonist of it is given results in early pregnancy, a higher rate of miscarriages in humans is seen.
In rats which were ovariectomized and then given estradiol, there was an increase in the production of anandamide, showing that estradiol has a direct impact on its production as well as regulating its degradation. In summary, though more complex than what will follow, as the two systems have multiple pathways of interconnectivity, it appears that estradiol modulates the receptor activity, the production, and the degradation of the endocannabinoids, both in the CNS and peripherally. In turn, the endocannabinoids downregulate the production of estradiol by decreasing the release of gonadotropins.
Estradiol administration in female rats elicits anxiolytic and antidepressant-like effects. Studies show that the impact on emotions which are due to estradiol are elicited through the endocannabinoid system. Research on the emotional and behavioral effects involved in the interplay between the endocannabinoid system and estradiol show that estradiol incorporates the endocannabinoid system in its behavioral effects and can down-regulate FAAH activity in the CNS, thereby increasing the levels of anandamide. Further confirming these findings are studies showing that when a CB1 receptor antagonist was given to rats, the anxiolytic effect of estradiol was blocked, and when a blocker of FAAH (the enzyme which degrades anandamide) was given, and levels of the endocannabinoid rose, and an anxiolytic effect occurred, precisely like that produced by estradiol.
Brain endocannabinoids have been recognized as major modulators of affect, motivation, and emotions, and the emerging connection to estradiol, and the other sex hormones, is only recently emerging and must now be recognized for their great significance in the functioning of this critical body system. We live in a world of endocrine disruptors, including pharmaceuticals which in fact are endocrine disruptors themselves – such as metformin, oral contraceptives, “hormonal” IUDs and implantables – and we should additionally recognize the inevitable and universal impact of menopause on the endocannabinoid system and its impact on women’s emotional regulation.
With the recent recognition of the critical and complex bidirectional effects of the endocannabinoid system and the dominant female hormone – estradiol, and of the impact of marijuana and other cannabinoids, including the heightened susceptibility of women to their effects of dependency – we have entered a new era, a new future filled with many potential opportunities both for the benefit and for the detriment of women. We must now begin our journey with the attainment of a solid knowledge-base of the endocannabinoid system, and an understanding of its complex role in reproductive, emotional, and immune health in women. We are obligated to provide in-depth education for women, to enable them to assess their risk of both the potential for good and for harm from their contraceptive choices, pharmaceuticals used, exposures to endocrine disruptors, and equip them with the ability to make good decisions regarding their use of marijuana for recreational use, as well as appropriate use of medicinal cannabis. And for us, the medical professionals, we will always stay cognizant of the intricate bidirectional systems involving estradiol and the endocannabinoid system, recognizing the interplay of these systems and of their implications for mental wellbeing.
Does CBD Increase Estrogen?
For women, estrogen is an incredibly powerful player across many pathways.
Of course, there’s the question of estrogen levels and certain cancers.
Researchers know that the endocannabinoid system is intimately wrapped around steroidal hormones.
Let’s get into it.
We’ll cover these areas:
- The endocannabinoid system and estrogen
- CBD versus THC for estrogen levels
- Does CBD increase estrogen
- Can CBD help balance estrogen
- Can CBD help with estrogen dominance
- CBD and estrogen-positive cancer
- Does CBD contain estrogen
The endocannabinoid system and estrogen
Researchers are only not unraveling the complex and many relationships between our endocannabinoid system and steroidal hormones (including estrogen, testosterone, and progesterone).
Clues have been found along the way and the effects can be different between the genders.
That’s our first clue since estrogen has brain modulating effects in males but a superstar in the female body across almost every system.
Completely opposite effects have been seen in sexual behavior such that cannabinoids facilitate female but impair male sexual activity.
Let’s first take a step back to understand the role of the endocannabinoid system and then introduce estradiol (E2 – our most prominent flavor of estrogen).
The endocannabinoid system dates to about 600 million years ago in evolution and every animal you see has one.
It’s generally tasked with balancing other key systems from stress:
- Nervous system – neurotransmitters like serotonin, GABA, and dopamine
- Immune system – inflammatory response agents like microglia and cytokines
- Endocrine system – both steroidal (estrogen) and metabolic
Did you catch the last one?
By stress, we mean the general type. anything internal or external that pushes the system one way or the other.
The endocannabinoid system works like a feedback system to right the ship.
What about steroidal hormones like estrogen?
While the ECS is known to modulate pain and neurodevelopment, it is also known to impact the female reproductive system where it affects folliculogenesis, oocyte maturation, and ovarian endocrine secretion.
“Ovarian endocrine secretion”. That’s estrogen and progesterone!
There’s a direct tie between one of our most powerful endocannabinoids called Anandamide and estrogen.
A bi-directional relationship really.
There was a significant correlation between plasma AEA and E2 (P = 0.022), but not between plasma AEA and serum P4, in non-pregnant women.
So progesterone is off the hook (for non-pregnant women) but estradiol is intimately tied to anandamide.
In fact, anandamide levels ebb and flow during the monthly cycle just like estrogen.
FAAH breaks down anandamide so this would result in an inverse relationship with estradiol.
There are two kinds of endocannabinoid receptors in the body:
- CB1 – prominent in the nervous system
- CB2 – prominent throughout the body including the immune system
If we go up to the hypothalamus, the master controller of estrogen production, we see a direct effect via these receptors.
Let’s go up the chain to GnRH (gonadotropin-releasing hormone).
It’s a mouthful but this manager of estrogen production (as well as progesterone and testosterone).
Here’s the connection that’s important to us.
CBs block the pulsatile release of GnRH. When a CB receptor agonist is delivered into the third ventricle of adult female mice, estrous cycles are prolonged by at least 2 days.
Basically, direct stimulation of CB1 receptors will downregulate the whole steroidal hormone (including estrogen) process.
Anandamide is the main driver of CB1 activity.
Guess what cannabinoid can imitate anandamide in the body?
CBD versus THC for estrogen levels
It’s been established for a while that THC can interfere with the entire steroidal hormone system including the net effects on reproduction.
THC directly stimulates (like lock and key) the CB1 receptor just like CB1.
There are definite differences in response by gender.
Consistent with this, females are more sensitive than males to the adverse effects of escalating THC exposure during adolescence on emotional behavior and stress reactivity in adulthood.
In fact, THC interferes with the process at the very top of the chain. pregnenolone.
Pregnenolone is the raw material for ALL our steroidal hormones.
THC’s effect there?
THC also inhibits steroidogenesis by preventing the conversion of pregnenolone to progesterone.
Steroidogenesis is the process of making hormones like estrogen.
There’s lots of research on THC’s effect in this process.
What about CBD? Does it directly stimulate CB1 receptors in the same way as THC?
This is beauty of CBD we see across different pathways.
Here’s the distinction:
- THC is a direct agonist of CB1 receptors
- CBD is an inverse agonist of CB1 and CB2 receptors
- CBD is also a negative agonist modulator
Goodness.what does all that mean?
Agonist just means that it promotes (as opposed to blocks) activity.
THC is a partial agonist for CB1-R and CB2-R; CBD is an inverse agonist for both.
That third one is important. It basically says that CBD will slow down other chemicals that push in one direction.
A dampening field if you will.
Okay. what does all that mean?
Basically, THC directly spurs activity in one direction.
CBD works as a restraint on activity. like a rubber band.
It’s a signal backwards like a feedback mechanism.
This is why we don’t see overdoses on CBD.
You can definitely overdose on THC (see CBD and greening out) or any chemical that pushed in one direction (see CBD versus benzos or CBD versus SSRIs).
This speaks to the heart of the endocannabinoid system in finding “homeostasis”. a fancy word for balance.
Interestingly, THC itself may reduce estrogen but cannabis smoke appears to be estrogenic:
MSC stimulated the estrogenicity related to the ER-mediated pathway, while neither THC, CBD, nor CBN did.
MSC is short for marijuana smoke condensate.
Just a head’s up if you use cannabis (male or female).
So let’s get into directly based on research.
Does CBD increase estrogen
In most pathways, CBD has the opposite effect of THC.
CBD acts as a partial agonist for GPR18 and GPR55 and antagonizes the effects of THC.
Can we find specifically on CBD and estrogen?
One very old study found a reduction in estrogen but at very high levels.
We prefer newer research since the techniques are so much more sophisticated now.
Above, we referenced the study that showed marijuana smoke was estrogenic but CBD itself was not.
This is generally attributed to the other substances found in cannabis (and potentially full-spectrum CBD in hemp oil).
The direction may be the other way (more prominently).
Estradiol directly influences the levels of endocannabinoids.
One study found no binding of CBD to estrogen receptors in living things (as opposed to in a test tube):
Neither Δ9-THC, desacetyl levonantradol, nor cannabidiol stimulated transcriptional activity.
What we do know is that estrogen has powerful effects on cannabinoids and their receptors.
A recent report has demonstrated that protein levels of the CB1 receptor are significantly lower in females relative to males.
They even found that women will use cannabis more after having ovaries (and hormones) removed.
It even goes right down to receptor activity present which can fluctuate during the cycle:
Our data are in accord with those of Mize & Alper (2000) who reported that estradiol replacement in OVX females decreased CB1 receptor-mediated G-protein activation in the hippocampus 2 hr following estradiol administration.
This has a huge impact on many other systems. especially mood and cognition (see CBD and perimenopause mood or CBD and perimenopause brain fog).
So. the research is pointing to Anandamide and THC’s direct effect on reducing estrogen levels:
Lower concentrations of GnRH [and consequently a decrease in LH and follicle-stimulating hormone (FSH) concentrations] result in lower circulating estrogen levels.
Estrogen in turns increases the levels of cannabinoids.
CBD does not appear to have a direct effect on estrogen levels.
We’ll look at this further in our CBD and estrogen-positive breast cancers where there’s more research.
Can CBD help balance estrogen
We’ve looked at CBD’s effects across many pathways with interesting results but asking for CBD to balance estrogen levels (to progesterone or testosterone) is not yet supported in the research.
We’re all about research.
There is research for balancing of other hormone pathways (insulin, metabolic, etc).
PCOS (polycystic ovarian syndrome) is a disease born out of hormone imbalance but it also has a metabolic bent (insulin figures strongly) so we can’t fall back on that.
Check out our reviews on fisetin and berberine as there’s interesting research for both on PCOS.
It’s important to get a Dutch test or equivalent to really understand your hormone profile.
In the end, hormone balance is driven by many factors (weight, genetics, stress, etc).
We’ll keep an eye out for new research on the complicated relationship between our endocannabinoid system and steroidal hormones.
Here’s a graph of just a few pathways between the two:
There are tantalizing clues that endocannabinoids partially regulate the hormone pathway.
Let’s go upstream to GnRH which manages estrogen levels:
These lipids, in turn, could bind to CB receptors on neighboring cells, and perhaps GnRH neurons, to exert feedback control over GnRH function.
Goodness. this goes directly to balancing estrogen and other steroidal hormone levels.
Feedback control is the key there as we find throughout the literature.
A slightly different way of asking this question.
Can CBD help with estrogen dominance
This is a common question and usually speaks to estrogen’s relationship with progesterone.
There’s a fine balance between the two as progesterone is generally a calming agent against estrogen’s pro-growth effects.
As with the section above, we have not seen research where CBD directly affects this balance.
Check out our review on pregnenolone which is the precursor for all steroidal hormones but with a strong effect on progesterone.
This doesn’t imply that it will substitute for supplementation of progesterone, however.
If you check our estradiol review, you’ll see just how important these hormones are to every pathway we have.
Dutch test (to see how the body ACTUALLY processes these hormones) and adjust accordingly is my baseline these days (in perimenopause).
Let’s look at the cancer angle now.
CBD and estrogen-positive cancer
This really requires a separate full article as there’s a great deal of research.
Some cancers are driven by estrogen levels.
The effects of CBD and cannabinoids may be more about the birth/death cycle of cells than the actual impact on hormonal pathways.
CBD’s effect on cancer is fascinating and speaks to its role in supporting balance in other key systems.
First, the direct effects:
Finally, a recent study showed that CBD induces concentration-dependent cell death of both oestrogen receptor-positive and oestrogen receptor-negative breast cancer cells through a mechanism involving a CB1-, CB2-, and TRPV1-independent receptor activation.
Here’s the really fascinating piece.
CBD’s effect will depend on the state of the cell (again, about balance).
Researchers put it this way:
Although CBD was found to reduce the formation of ROS and NO in various cell lines and animal models of inflammation, there are also reports showing that CBD can induce ROS formation in cancer cells, leading to cytotoxicity.
ROS is short for reactive oxygen species. oxidation (see CBD and oxidative stress).
Basically, the effects were threefold:
- Normal cell with low oxidative stress – no effect
- Normal cell with high oxidative stress – reduce oxidation
- Cancer cell – INCREASE oxidation!
This is amazing. Here’s why…
The body (and chemo or radiation) uses oxidation to kill cells that appear faulty.
We have an entire system for detecting and killing pre-cancerous or cancerous cells.
The coolest part? This study came from breast cancer studies.
The study is here:
CBD unleashed a slew of cellular damage on cancerous cells but not on surrounding healthy cells.
This may be one of our favorite studies as it points to the true role of the endocannabinoid system.
Finally, one question that comes up.
Does CBD contain estrogen
CBD does not contain estrogen.
Similarly, it has not been shown to increase estrogen.
THC may suppress estrogen levels while cannabis smoke may be estrogenic.
CBD operates as a constraint on THC’s effects (see CBD versus THC).
Technically, a reverse negative modulator.
That’s fancy talk for….feedback mechanism!
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.
Hello Ann. Here’s the promised review of CBD and turkey tail for cancer.
One note…full spectrum products (CBD or THC) may have some plant materials that promote or mimic estrogen. Terpenes and other plant chemicals can have this effect (similar to soy). That’s why we focus on CBD isolate which does not affect estrogen or progesterone.
We have research on CBD isolate but we can’t speak to full spectrum since there’s just not great studies out there. There are various plant materials that can mimic estrogen but no one has looked at full spectrum in detail. More importantly, studies on cancer point to very different responses between CBD isolate and full spectrum.
On a side note, there are some interesting ways to protect against high estrogen which are readily available depending on why you’re looking to avoid estrogen.
Estrogen has two main receptors: a or alpha and b for beta. Many people are avoiding estrogen for the alpha aspect (pro-growth) such as with specific cancers. Beta can actually be protective against this effect such as with Siberian Rhubarb or the SERMs like tamoxifen (for breast cancer, etc). Lots of research from Europe on Siberian rhubarb. Of course, progesterone is the big countering force to estrogen in the body. It drops by 50% at age 40 and is a huge deal across every pathway of the body. See our estrogen review. There’s a lot of estrogen dominance pushed out there in healthcare which generally amounts to inadequate progesterone. You can get a Dutch test to really see how your body is processing both. For men, it’s a question of blocking or inhibiting aromatase which converts testosterone to estrogen. There are some naturals to do that although we’re not as well versed.
Thank you so much for this article. Do you know if there’s any difference on estrogenic effects (like for a male OR an estrogen-dominant female, both trying to avoid anything estrogenic) between broad-spectrum CBD and CBD isolate? I’ve read that terpenes and possibly other compounds in broad-spectrum may be estrogenic.
Wow, I am very intrigued, but am left a little confused. I have been battling metastatic estrogen and progesterone positive breast cancer for 3 months. I do take CBD products and cannabis edibles, so I am very interested in knowing whether any of these can increase (or decrease) estrogen and progesterone in the body (or the receptors). Thank you for the article.
Does Hemp Protein Contain Estrogen?
No, hemp protein does not contain estrogen. As hemp foods have no phytoestrogen properties, hemp products don’t have an impact on estrogen levels one way or the other. However, hemp seeds do have a positive impact on hormonal health since they are chock-full of fibre, minerals, vitamins and essential amino and fatty acids.
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