If you've studied a few 1000 hours on anxiety-like we have, something occurs over time.
You see depression shares many of the same pathways in the brain.
This is equally true for depression that results from perimenopause.
We're going to look at that entire circuit with the goal of trying to affect those very pathways.
24/7 anxiety was my initial "Hello!" from perimenopause but bouts of depression definitely rolled through occasionally.
Then there's the severe depression that resulted from Lexapro which crushed me (that story is here).
So what's going on?
Can perimenopause cause depression or can it make it worse?
Yes!
We'll look at two different aspects of it, both with ties to hormones.
We need to stop looking at hormones (estrogen and progesterone primarily) as simple tools for reproduction.
You have receptors for either on almost every type of cell in your body...especially neurons.
Wait till you see what they get up to there in terms of the depression pathway.
There are fascinating new discoveries (such as the new post-partum depression medication) we can use in our favor.
The endocannabinoid system (where CBD works) has its signature all over this pathway!
We'll then turn our attention to things that can help with these pathways tied to perimenopause depression.
The topics are as follows:
- What is depression
- How does perimenopause cause depression
- Hormones and perimenopause depression
- Antidepressant medications versus CBD for perimenopause depression
- The endocannabinoid system and depression
- Can CBD help with perimenopause depression (plus other aids)
- Other aids for perimenopause depression
- How much CBD for perimenopause depression
- The best CBD for perimenopause depression
Stay with us...especially if you're in a bad place. Let's see what research is showing here.
What is depression
We're only going to give a rough sketch based on new research so we can focus on perimenopause.
There's a great review of current understanding here:
https://www.health.harvard.edu/mind-and-mood/what-causes-depression
The key brain areas tied to depression are:
- The prefrontal cortex - rational thought and seat of "you" - too little activity is tied to depression
- Hippocampus - memory and mood regulator - too little activity or volume is tied to depression
- Amygdala - emotional processing area - too much activity tied to depression (and anxiety)
- Thalamus - the connector between "ancient" and "new" brain - more tied to bipolar
There are obviously multiple facets that play into the depression circuit but there's definitely been a change if you're keeping up with new research.
First, it's not all about neurotransmitters like serotonin (see CBD versus SSRI's for serotonin here).
Yes, they're important foot soldiers in the brain but if they were the only piece, people's moods would immediately respond.
It generally takes a few weeks for their effects to kick in (when they do).
This then speaks to what is really happening.
Under optimal situations, your brain is highly connected and "entangled" across areas and with neighboring neurons.
It's highly integrated.
A lot has to work to make this happen!
- There are the actual building and repairing of neurons and pathways.
- There's suppression of new damage from stress, infection, chemicals, drugs, and immune response
A chink in either of these components can cause retrenchment.
Think of depression as retrenchment...a pulling back of the actual brain from itself.
The clues to this are everywhere including the common SSRIs prescribed.
Why do they take a few weeks to kick in if the serotonin level goes up right away?
New research is showing that their true effect is neurogenesis.
Neurogenesis means to build new brain connections!
The Effect of Serotonin-Targeting Antidepressants on Neurogenesis and Neuronal Maturation of the Hippocampus Mediated via 5-HT1A and 5-HT4 Receptors
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432636/
5HT is another word for serotonin.
Did you catch where that's happening?
The hippocampus...a key area tied to depression and also the most vulnerable part of our brain to stress, inflammation, and anxiety.
It's the seat of our memory and a key regulator of mood.
We've covered it in detail with anxiety (hence the shared prevalence).
In fact, the "comorbidity" or chance of having both is significant:
Some estimates show that 60% of those with anxiety will also have symptoms of depression, and the numbers are similar for those with depression also experiencing anxiety.
https://www.nami.org/Blogs/NAMI-Blog/January-2018/The-Comorbidity-of-Anxiety-and-Depression
Check out CBD and hippocampus neurogenesis for more information.
Maybe more fascinating is this…
The actual pathway that this neurogenesis is dependent on resides in the endocannabinoid system, where CBD does its work!
Researchers genetically "knocked out" CB1 (the primary endocannabinoid receptor) and SSRI's lost their antidepressant effect:
Moreover, CB1 knockout mice displayed functional impairment of 5-HT1A and 5-HT2A/C receptor-mediated neurotransmission in the hippocampus [117] while a loss of antidepressants behavioral effects were described after genetic blocked of CB1 receptors
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648779/
BDNF is also a powerful player in this rebuilding effort. Check out CBD and BDNF for neurogenesis.
In the opposite corner, we have stress, inflammation, immune over-response, and other chemicals.
If serotonin and BDNF are busy trying to repair, rebuild, and repath our brain circuitry, they're under the constant assault (and even some from childhood, the womb, and prior generations!!).
Stress and inflammation have been shown to actually cause brain loss!
Our immune system's overreaction can also wreak havoc.
Check out the following:
They're targeting anxiety (our first love/hate) but the effects are the same for depression.
What are some clues that depression is a result of a mismatch between insult/repair?
Just a few:
- Excercise
- Psilocybin
- Hormones (could be important for perimenopause??)
Exercise is known to have a powerful antidepressant effect:
Based on this reassessment, RCTs comparing exercise to antidepressants reported that exercise and antidepressants were equally effective.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430071/
In that same article, they point to BDNF (our brain's fertilizer) and serotonin as the key reasons for this effect.
The opposite of retrenchment (trenchment???).
Then there's the curious case of psilocybin.
That's the active chemical in psychedelic mushrooms which is getting much more attention these days for depression:
Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial
https://journals.sagepub.com/doi/pdf/10.1177/0269881116675513
Most interestingly, the antidepressant effect from one dose can last for extended periods of time.
Look...this substance is still illegal (outside of Colorado and Oakland, CA) but it's interesting in terms of understanding the pathways.
What does psilocybin do?
It's a powerful explosion of neurogenesis via serotonin and BDNF pathways.
Really, it's BDNF doing all that heavy lifting.
In fact, when they block a key pathway for BDNF function called TrkB, the neurogenesis goes away:
A selective antagonist of BDNF’s high-affinity receptor TrkB, the ability of psychedelics or BDNF to stimulate neuritogenesis and spinogenesis was completely blocked (Figure 4).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082376/
We absolutely love BDNF after doing a full review of it here at our CBD, BDNF, and neurotrophins.
Finally, hormones!
Your sex or steroidal hormones such as estrogen and progesterone.
We're going to get into this below but the quick snapshot:
A study from the University of Albany found that the administration of the hormone estradiol to aged female mice decreased anxiety-like and depression-like behaviors.
https://www.psypost.org/2010/02/study-finds-link-between-estradiol-and-depression-anxiety-232
Estradiol is your primary estrogen.
This can definitely figure into the higher risk women have:
The National Comorbidity Survey (NCS) found that, between the ages of 15 and 54 years, the lifetime prevalence of MDD is 12.7% for men and 21.3% for women
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440795/
MDD is Major Depression Disorder. Booooo!
Ladies...we have to help each other because the signs are EVERYWHERE:
The peaks of depression occur at times of hormonal fluctuation in the premenstrual phase, the postpartum phase, and the climacteric perimenopausal phase, particularly in the 1 or 2 years before the periods cease.
What a great segue into perimenopause (if there is such a thing).
Buckle your seats, it's going to get bumpy!
How does perimenopause cause depression?
Perimenopause is a significant flux in key hormones.
Other key "upstream" hormones and precursors are also spiking and dropping (see Pregnenolone here).
The real flux is with estradiol (our workhorse estrogen with which we refer to interchangeably) and progesterone.
Those are the two hormones that govern our monthly cycle.
The problem is that our medical community simply sees estrogen and progesterone as methods of reproduction.
Once you've had babies, EXPENDABLE!!
Seriously, when I walked into my GP and OBGyn, they looked at my zero progesterone and barely detectable estrogen (not even an estradiol breakout) and said…
"That's normal for your age. The standard for menopause".
A...I was suddenly coming out of my skin (that story here) and B...I still had my PERIOD!!!
Goodness, if I had a conspiratorial bent, I would say the medical community doesn't care about women beyond birth.
I digress (and unclench).
Estradiol and Progesterone are tied into every major system in your body and brain.
They actually start to go down early 40's and even late 30's (especially progesterone).
As we approach perimenopause, progesterone generally drops first (not produced if an egg is not created) even while we have periods still.
Estradiol will generally follow this trend afterward.
Here's the deal...it's not always a clean approach to the runway!
There can a spastic cat and mouse effect between estradiol and FSH which is trying to prop up ovarian production of estrogen as it runs out.
This can result in a pretty severe roller coaster effect in hormone production.
Keep in mind that your body (and every cell in it) has been used to pretty reliable cycles for a good 3 decades with intermittent blips (pregnancy, nursing, birth control, etc).
You're suddenly upsetting the apple cart and depression is a common effect of this.
A number of cross-sectional and longitudinal studies (Table 1) have evaluated the relationship between the menopausal transition and an increased risk of mood disorder
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882813/
The list of studies in that link go back decades and you're not alone:
It has been estimated that 20% of perimenopausal women present to their primary healthcare physician with depressive symptoms
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023883/
Women are notoriously bad in actually getting help for mental health issues so the number is likely quite higher.
Interestingly, perimenopause depression can be different from the early years of depression.
It can come in waves, last minutes or hours, and also exhibit along with irritability, anger, and then go away!
I personally felt this on and off again effect.
The question then becomes...why do some women get hit so hard (hi, my name is Andrea), while others seem to skate through?
We'll get into that below in the endocannabinoid system section. Very fascinating!
The primary theory is that of hormone fluctuation driving these mood swings.
Research bares this out:
The hypothesis that fluctuations in sex hormones marking female reproductive events could influence neurochemical pathways linked to depression is extensively supported by animal and human studies and existing clinical data
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440795/
Don't take our word for it...let's drill down into the pathways of perimenopause depression.
We're going to look specifically at the actors and pathways affected.
We'll start with estradiol (estrogen).
Estradiol and perimenopause depression
Look...every website out there has a general statement on how hormone fluctuation can drive depression during perimenopause.
If you've looked at our article on CBD and perimenopause anxiety, you'll see that's not going to work for us.
We want to know why?
Get ready to have your mind blown (or we'll settle for less depressed).
We discussed briefly how depression is a general "retrenchment" of the brain with stress response and brain repair pathways in a tug of war.
A more eloquent description is here:
An astounding number of factors could be responsible for the derailed mood infrastructure - dysregulation of inflammatory, metabolic, neuroendocrine, growth factor and of course, neurotransmitter systems, just to name a few
https://www.zrtlab.com/blog/archive/impact-hormones-serotonin-depression/
Serotonin and BDNF figured strongly in this calculation under the "growth factor" heading.
Serotonin first.
Serotonin, Estradiol, and Perimenopause Anxiety
That link above is a beautiful run through of serotonin and estradiol but some key takeaways.
Serotonin is our brain (and gut) workhorse, communicator.
They call it the "feel good" neurotransmitter mainly because if it's not working correctly, you're going to feel some version of terrible (depressed/anxious with too little...irritable/impulsive with too much).
You have tryptophan on the front end (to make serotonin) and MAO to break it down.
Does estradiol have any impact at those two constraints?:
Estradiol is especially nurturing towards serotonin – it stimulates TRPH expression to ensure that enough serotonin is made and suppresses MAO A levels to prolong the longevity of the neurotransmitter.
https://www.zrtlab.com/blog/archive/impact-hormones-serotonin-depression/
It governs serotonin levels by keeping a hand on the production and removal of it!
We could literally end this article right there.
Most doctors will prescribe an SSRI like Lexapro or Effexor to juice up the Serotonin levels for women in perimenopause but the side effects can be brutal.
Check out CBD versus SSRI's for serotonin.
The net effect of this resulting drop specific to our discussion:
This relationship between estradiol and serotonin is prominently featured in perimenopause, when estradiol levels eventually plummet, leaving serotonin down in the dumps as well.
Remember how perimenopause depression can be different in that it may pop up out of nowhere and then disappear as suddenly?
We conclude that estradiol may have a fast, direct effect on brain membranes to modify serotonin receptor availability while exerting a slow effect on the same receptors through interaction with intracellular estrogen receptors in those brain regions that contain them.
https://www.jneurosci.org/content/2/2/199.short
So both immediate and long term effects on depression.
Serotonin governs many different aspects of our health besides stress response (ummm...important):
Serotonin regulates appetite, temperature, energy balance, platelet coagulation, bone remodeling, sleep cycles, emesis, the inflammatory response, and sexual behavior, just to name a few
https://www.ncbi.nlm.nih.gov/pubmed/25439045
Let's see...do any of those tie in with common perimenopause symptoms:
- Weight gain
- Hot flashes
- Fatigue
- Sleep disruption
- Nausea (emesis)
- Low libido
Goodness. And estradiol has its hand on the master switch of this "housekeeping" neurotransmitter!
Just a head's up...most of our serotonin is made and operates in our "second" brain...the gut.
These gut-resident cells produce much more 5-HT than all neuronal and other sources combined, establishing EC cells as the main source of this biogenic amine in the human body.
https://www.ncbi.nlm.nih.gov/pubmed/25439045
It's key to managing inflammation in the gut which quickly becomes inflammation in the brain (Alzheimer's, Dementia, Anxiety, depression, etc).
Check out CBD and neuroinflammation to see how powerful an effect this can be.
We'll look at that side of the equation but first, our brain's fertilizer....BDNF.
Estradiol, BDNF, and perimenopause anxiety
BDNF (see CBD, BDNF, and Brain Repair) is our brain's fertilizer:
Brain-derived neurotrophic factor (BDNF), which is known to play an important role in development, maintenance and plasticity of the brain, especially in these regions may ultimately contribute to cognitive function
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597766/
We've written extensively on anxiety and BDNF keeps popping up over and over again.
Whether it's PTSD, OCD, or General Anxiety Disorder...BDNF is lurking somewhere behind the curtains.
Depression is no different.
In fact, the net net effect of SSRIs prescribed for depression is pointing to...BDNF!:
Antidepressant treatment for at least four weeks can restore the decreased BDNF function up to the normal value.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022308/
These alterations of BDNF levels or neuronal plasticity in MDD patients before and after antidepressant treatment can be measured through the examination of serum or plasma BDNF concentrations.
This speaks to depression reflecting a "rigidity" in brain networking.
This rigidity taken to an extreme:
Suicidal behavior can be a consequence of severe impaired neuronal plasticity in the brain.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022308/
Okay okay..BDNF is important (remember, it was THE key to psilocybin effect).
Does estradiol affect BDNF pathways?
Generally, increased levels of estrogen are related to greater dendritic spine density on pyramidal cells in the PFC and hippocampus and to improved memory function.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597766/
Think of the "spine density" as little branches and roots that spike off of neurons to form new connections.
The opposite of a retrenchment!
PFC is the prefrontal cortex, our rational brain and the seat of what makes you, You.
Impaired activity in this region has been tied to depression across a range of studies.
In fact:
Repetitive transcranial magnetic stimulation of the dorsomedial prefrontal cortex (dmPFC) and dlPFC exhibits effectiveness and safety in treatment-resistant depression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299163/
That's for people where nothing else is working!
And the hippocampus??
A summary of many different brain scan studies found:
Hippocampal volume is reduced in patients with unipolar depression, maybe as a consequence of repeated periods of major depressive disorder.
https://ils.unc.edu/bmh/neoref/nrschizophrenia/jsp/review/tmp/127.pdf
Check out CBD and hippocampus neurogenesis
So...the net net is this...estrogen boosts BDNF levels in two of the critical areas tied to depression.
In fact...they could tie levels of estradiol, BDNF and a host of related effects:
In adult females, fluctuations in recognition memory following ovariectomy and estradiol replacement, during the estrous cycle, in pregnancy, and with aging are accompanied by similar changes in circulating estradiol, BDNF levels and spine density alterations in the PFC and hippocampus.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597766/
Brain fog anyone?? Check out CBD and brain fog.
To put a cherry on top, Serotonin and BDNF are intimately interlinked and a drop in one results in a drop of the other.
Think of serotonin as the quick fix agent while BDNF's process of building is slower.
That's why it can take a few weeks for SSRIs to even kick in.
So that's the repair side...what about stress response to avoid the damage, to begin with?
Estradiol is critical to protecting the brain from neuroinflammation.
Why do women have a higher risk of autoimmune diseases after perimenopause?
Is there a connection?
Human epidemiological data, animal studies, and mechanistic experiments have demonstrated a strong link between endocrine transition states in women and the development of certain autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, type 1 diabetes mellitus, rheumatoid arthritis, and psoriasis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501433/
Endocrine is the fancy word for hormones...i.e. estradiol and progesterone.
The keyword there is "transition".
Autoimmune is basically when the body's immune system becomes too aggressive and actually starts to attack good tissue instead of infection or foreign bodies.
We have a huge review of CBD and autoimmune since the gender and timing of diagnosis is suspicious with perimenopause.
Then there's the brain's immune responders...microglia.
Where does all that repair that BDNF needs to do come from?
If microglia are hyperactive, that's a good source of inflammation and destruction.
Does estrogen have a role there?
Estrogen has a role EVERYWHERE!:
Systemic administration of hormone prevents, in a time- and dose-dependent manner, the activation of microglia and the recruitment of peripheral monocytes induced by intraventricular injection of lipopolysaccharide.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC170966/
You see this across every inflammatory pathway (and there are 1000's) in the brain and body.
Just one specific example to show how complex it can be:
In addition, other inflammatory pathological conditions, such as wound healing (1), atherosclerosis (for a review, see reference 18), ischemia (10), uveitis (28), and leukodystrophy (27), were shown to be influenced by E2, which decreased disease susceptibility, severity, and damage.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1069609/
E2 is estradiol, our most prevalent and powerful flavor of estrogen.
We brought this study up specifically (out of dozens) since bogus reports with old information still point to estrogen supplementation as a risk for stroke (ischemic), heart issues (atherosclerosis).
That was from horse derived or synthetic estrogens!
Goodness, catch up with the research (and go bioidentical of course).
My 3rd doctor (that story is here) warned me (both hands gripping my arms in the hallway), "You're going to have a stroke" from hormone supplementation.
This was the same doctor who prescribed Lexapro (SSRI) which almost broke me and synthetic birth control for estrogen and progesterone.
Keeping up with the research is so bad out there that we wrote a comprehensive review on estradiol for perimenopause here.
Anyway...back to estradiol and perimenopausal depression.
We bring all this up for this reason:
Patients with chronic inflammation are often associated with the emergence of depression symptoms, while diagnosed depressed patients show increased levels of circulating cytokines.
https://www.frontiersin.org/articles/10.3389/fncel.2015.00476/full
Cytokines are little inflammatory agents running amok (when excessive).
One final mention of estradiol that's the key to protecting the brain.
Estradiol and stress response.
To put a point to it:
Estrogen is likely involved in the gender-specific differences in coping with stress.
https://www.sciencedirect.com/science/article/abs/pii/S0306452205000369
In fact, it lies at the heart of controlling how our brain/body responds to stress...the so-called HPA (Hypothalamic - Pituitary - Adrenal) axis.
Just one example that's important to perimenopause.
In one study, they showed how estradiol brought down the blood pressure response in rats with ovaries removed from a stressful situation:
In a parallel experiment, BP was monitored during restraint stress. The elevation of BP in response to single or repeated restraint stress was sustained during 2 h in controls and reduced after 70 min stress in EB treated rats
https://www.sciencedirect.com/science/article/abs/pii/S0306452205000369
EB is the estrogen treatment.
We'll wrap it all up in a bow for you.
In a brand new study:
The menopause transition is associated with an increased risk of depressed mood. Preliminary evidence suggests that increased sensitivity to psychosocial stress, triggered by exaggerated perimenopausal estradiol fluctuation, may play a role.
Okay. So what did they find specifically?
E1G fluctuation was positively associated with anhedonic depressive symptoms and weekly negative affect. E1G fluctuation was also associated with increased heart rate throughout the TSST as well as higher levels of rejection, anger, and sadness.
Basically, as estrogen went down, depression and lack of joy went up!
Also, anger, sadness, and a sense of rejection with increased heart rate (poorer stress response).
https://www.frontiersin.org/articles/10.3389/fpsyg.2019.01319/full
Maybe, more importantly, you're not alone! You're not weak. You're not wrong.
A recent review article identified 12 cross-sectional studies comparing rates of elevated depressive symptoms in pre- and peri-menopausal women and concluded that 45–68% of perimenopausal women, versus only 28–31% of premenopausal women, report clinically significant elevations in depressive symptoms
45-68% - clinically significant depressive symptoms.
There are MILLIONS of us out there and no one's talking about this.
You should be going from depressed to angry right about now.
So that's a brief introduction to estradiol for perimenopause depression.
Next up...the counter-balance...Progesterone.
Progesterone and perimenopause depression
First, we absolutely have to separate out synthetic progesterone (called progestins and found in most birth controls and even hormone replacement).
Just looking at the breast cancer question since that's been the big boogeyman stemming from the 2002 study that misleads and scared the bejesus out of millions of women:
Progesterone was associated with lower breast cancer risk compared to synthetic progestins when each is given in combination with estrogen, relative risk 0.67; 95 % confidence interval 0.55–0.81.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960754/
33% difference in risk!
There's a great review that's easy to read and understand here:
https://www.larabriden.com/the-crucial-difference-between-progesterone-and-progestins/
Many studies point to various risks of hormones including progesterone but they're looking at synthetics.
Let's take a step back and look at what progesterone (the natural substance) does in the depression circuit.
Keep in mind that progesterone starts to drop in the '30s and it leads the charge (down) in perimenopause.
In fact, your progesterone may drop to near nothing even before your periods stop.
Just like estrogen, progesterone receptors are everywhere!
Even in the gut.
A study found that progesterone worked with gut bacteria in mice with ovaries removed to reduce both anxiety and depression:
Ovarian progesterone suppresses depression and anxiety-like behaviors by increasing the Lactobacillus population of gut microbiota in ovariectomized mice
https://www.sciencedirect.com/science/article/pii/S0168010219301427
The bacteria in question was Lactobacillus Reuteri.
Check out CBD and probiotics for a fascinating look at this special gut bacteria.
I can definitely second this effect.
When I take progesterone, I feel the effect in about 10-15 minutes.
I literally feel it when it hits my stomach as the liver takes a while longer to process.
The effects of progesterone are written heavily in the brain as well.
We looked quite a bit at the effect of damage (stress, inflammation, immune response, etc) and repair (serotonin, BDNF, neurogenesis) for depression.
Progesterone has a powerful neuroprotective effect.
Progesterone is a neuroprotective, promyelinating and anti-inflammatory factor for the nervous system.
https://www.ncbi.nlm.nih.gov/pubmed/23639063
We'll break those down a bit below.
Interesting studies looked at progesterone treatment after brain injury as an example:
Progesterone treatment reduces neuroinflammation, oxidative stress, and brain damage and improves long-term outcomes in a rat model of repeated mild traumatic brain injury
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-015-0457-7
Remember how autoimmune goes hand and hand with perimenopause and women in general?
A study was able to block the inflammatory signals of a severe autoimmune disease called encephalomyelitis where the immune system is basically attacking the brain:
Progesterone pretreatment of EAE mice blocked the proinflammatory mediators, decreased Iba1+ microglial cells and attenuated clinical signs of EAE.
https://www.ncbi.nlm.nih.gov/pubmed/23639063
In fact, progesterone calmed the immune response agents in the brain called microglia:
For instance, fairly recent studies have shown that progesterone, progestin or progestin metabolites could have the capacity to induce or inhibit neuroplastic changes by preventing microglia from releasing harmful free radicals
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335177/
We could go and on but progesterone has been found to be incredibly neuroprotective from the various insults tied to perimenopause depression above.
As for the fertilizer of the brain, BDNF:
Progesterone Increases the Release of Brain-Derived Neurotrophic Factor from Glia via Progesterone Receptor Membrane Component 1 (Pgrmc1)-dependent ERK5 Signaling
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423611/
Then there's the whole question of GABA and depression.
GABA is our "brake" and its immediate tie in is with anxiety (see CBD and perimenopausal anxiety).
Needless to say, anxiety is a common symptom with perimenopause.
Progesterone is directly tied to GABA function.
By both means of administration, progesterone significantly enhanced inhibitory responses of Purkinje cells to GABA and suppressed glutamate excitation within 3-10 min post-steroid. These results are consistent with the anxiolytic actions of the steroid.
https://www.ncbi.nlm.nih.gov/pubmed/2880640
Glutamate is the gas pedal and too much of it can damage brain areas. Anxiolytic just means anti-anxiety.
Why does GABA matter for depression?
Too much glutamate and too little GABA can be toxic to neurons!
Perhaps, the greatest effect of progesterone is its metabolite, allopregnanolone.
It's the basis for the new post-partum depression medication which is revolutionary in results but quite evolutionary in terms of origin.
Check out our full review on pregnenolone which you can get for $10 here.
The synthetic version of this is $25,000.
Our healthcare system is fine though.
Another key consideration...progesterone shows many counterbalancing effects to estrogen in the body.
This is turning up both in safety profiles for hormone replacement and across various pathways.
In general, estradiol is pro-growth and excitatory. Progesterone is anti-inflammatory and calming (hence the GABA connection).
A balance of the two is ideal and both are fluctuations during perimenopause.
Bearing all this in mind, let's look at the current state of medical help for perimenopause anxiety.
I've been on that train (hit by the train is more like it).
Anti Depression medications versus CBD for perimenopause depression
We've covered the main medications at our CBD and SSRI's.
In fact, the focus there was for anxiety but the primary focus of these drugs has been depression in general and perimenopause depression specifically.
In fact, after the benzo prescriptions, my doctor promptly put me on Lexapro.
Make sure to look at the side effects and understand how those medications work.
We did a full review at CBD versus SSRI's above.
They primarily boost serotonin which we've covered in detail above.
Serotonin is a workhorse neurotransmitter across the nervous system and gut.
Its real effect appears to promote neurogenesis as we saw in the estradiol section above.
It also drives BDNF which may actually be the real actor behind the controller.
Just educate yourself before any course of treatment.
I wish the doctor would have gone through the side effects and how difficult it was going to be to get off of Lexapro (see CBD to wean off SSRI).
It was tougher than the benzos and they're a known addictive drug with limited purpose once you see the research there (CBD versus benzos for GABA).
We go through all the research and pathways at those links above so we'll leave you with that.
Let's now get to an exciting area that researchers are just beginning to explore.
It's CBD's local neighborhood.
The endocannabinoid system and perimenopause depression
We all have this system.
It's about 600 million years old and we share it with every living animal (yes, you too, sea urchin!).
It's tasked with balancing other key systems:
- Nervous system - neurotransmitters like serotonin, GABA, and BDNF
- Immune system - microglia, gut bacteria, and autoimmune reaction
- Endocrine system - ummmm…..HORMONES!
Hopefully, we made that last category stand out.
If you're still with us this far (Thank you...there will be a pay off), perimenopause depression is all about hormones.
The chaotic flux and drop of them.
Ladies...this system may be your new best friend (after being your potential worst energy).
Homeostasis.
That's the technical word for balance.
It's the task of the endocannabinoid system with hormones and it's severely outgunned during perimenopause as estradiol and FSH are locked in a death spiral while progesterone quietly recedes in the background.
Thanks, mother nature!
Let's dig deeper.
We'll introduce you first to FAAH. It's a naturally produced endocannabinoid in your body right now.
Check out the review of the woman (past menopause by the way) who can't feel pain, anxiety, or….depression.
She has a genetic variant where she produces too little if any FAAH.
FAAH breaks down Anandamide, our "bliss" molecule named after Anand, the Hindu Goddess of Bliss.
What's the connection with estradiol?
Collectively, these data demonstrate that estrogen may elicit changes in emotional behavior through an endocannabinoid mechanism, and suggest that inhibition of FAAH represents a therapeutic target for anxiety and depression in women.
https://www.ncbi.nlm.nih.gov/pubmed/17391861
Let's walk through this because it's important.
It's one thing to say estradiol has anti-anxiety and anti-depressant effects.
It's another to find the exact mechanism and…
Find out it's the endocannabinoid system!
Furthermore, they were able to reduce estrogen's effect on anxiety and depression by blocking endocannabinoid receptors (CB1):
Interestingly, however, anxiolytic- and antidepressant-like effects produced by estradiol administration are attenuated by CB1R blockade [112], whereas estradiol administration increases AEA levels [113] or AEA signaling [114], possibly via downregulation of FAAH driven by an estrogen response element on the FAAH gene that suppresses FAAH transcription when bound by estrogen
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169112/
Oh...but estrogen's just for reproduction, silly women.
Now you see why we get angry when doctors hand out Lexapro scripts when a woman in her late 40's starts to lose it!?!?
It also speaks to why SSRI's are only effective in a percentage of the population (where there's a significant insult or lack of repair in their system).
This effect of estrogen belies a big part of its neuroprotective effect as found after stroke:
neuroprotection afforded by estrogen is coincident with reestablishment of anandamide levels in the ischemic striatum
Research here.
Okay...so what can do with all this information?
Good question….Great answers!
Can CBD help with perimenopause depression (plus other aids)
We've covered a lot above on perimenopause depression:
- Serotonin for balancing brain activity
- BDNF for brain repair
- Stress response
- Calming neuroinflammation
- FAAH and Anandamide levels
Let's look at CBD's effect on these pathways.
First, the repair pathways...Serotonin and BDNF.
CBD and serotonin for perimenopause depression
Remember that estradiol has its hands on the serotonin controls for both the creation and removal.
But estradiol is erratic during perimenopause and dropping soon after!
Easy enough:
The antidepressant-like effect induced by Cannabidiol is dependent on brain serotonin levels.
https://www.ncbi.nlm.nih.gov/pubmed/29885468
Two interesting items from this study.
First, they compared CBD versus Fluoxetine (Prozac) and a different class of antidepressant called a noradrenergic, desipramine
Results showed that CBD (10 mg/kg), FLX (10 mg/kg) and DES (5 mg/kg) induced antidepressant-like effects in mice submitted to FST.
https://www.ncbi.nlm.nih.gov/pubmed/29885468
Secondly, when they blocked serotonin pathways, the antidepressant effect went away for CBD and Fluoxetine.
The third med works on the adrenaline pathways.
This plays on the theory that there's not enough activity, especially in the prefrontal cortex which results in depression.
Remember...a brain retrenching!! (estradiol is pro-growth).
Here's the deal...SSRIs boost serotonin in one direction and there can be a nasty side effect to doing so.
Plus, the brain will "Normalize" or adjust in the opposite direction to the new boost.
Eventually, you have even less naturally-occurring serotonin.
That's why those drugs have to be cycled occasionally.
Does CBD do the same thing?
No! In fact, there isn't a reported CBD overdose on CBD isolate by itself.
How is this possible if it works on the serotonin pathways that SSRI's juice up?
If you're knee-deep in these studies for hours, you start to see a pattern in verbiage with CBD's effect on serotonin (or any pathways for that matter).
Here's an example:
Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319597/
"Normalized". Not increased. Not boosted indiscriminately. Normalized.
You'll see "Balance" and "Modulate" quite a bit as well.
In that experiment, they used the injury to throw serotonin firing off-balance. CBD corrected this effect.
Is there anything more off-balance than having progesterone ripped from us and watching estradiol spike and plummet for a few years?
Check out CBD versus SSRI's for serotonin or CBD and serotonin to get deeper into that.
What about BDNF...the nerve fertilizer?
CBD and BDNF for perimenopause depression
This may be our favorite study for this whole article:
Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex.
https://www.ncbi.nlm.nih.gov/pubmed/29869197
- CBD (Cannabidiol). Check.
- Antidepressant effect (rapid and sustained). Check.
- BDNF signaling (notice it didn't say boosting). Check.
- Synaptogenesis (building new brain pathways - the opposite of retrenching). Check.
- Prefrontal cortex (the part of the brain under assault with depression).
Goodness. Drop mic.
Remember that serotonin and BDNF have a close, supportive relationship but BDNF may be the real actor behind the curtain.
Check out CBD versus BDNF for brain repair.
That's the repair side.
What about stress response since estradiol and progesterone is under duress?
CBD and stress response for perimenopause depression
You only need to look at the CBD and public speaking study.
This was conducted on people with a diagnosed social anxiety disorder.
Check out CBD for public speaking or CBD for social anxiety.
The quick takeaway to show CBD's effects on stress response:
Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech
https://www.ncbi.nlm.nih.gov/pubmed/21307846
On a side note, the SSPS-N, a test showing a person's negative self-statement had ridiculous effects after CBD:
The SSPS-N scores evidenced significant increases during the testing of the placebo group that was almost abolished in the CBD group.
Abolished.
Check out CBD and negative thoughts for more information.
Look...the endocannabinoid system is key to stress response and even fear response:
Genetic manipulations that impede CB1R activation are anxiogenic [35], and individuals with eCB system gene polymorphisms that reduce eCB tone—for example, FAAH gene polymorphisms—exhibit physiological, psychological, and neuroimaging features consistent with impaired fear regulation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604171/
Let's translate this a bit.
When the genetically block CB1 receptors (endocannabinoid receptors in the brain), anxiety resulted.
In fact, people with genes that result in too much FAAH (more on that below) suffer from mood disorders like anxiety and depression.
Since both are common for perimenopause, you could argue that the endocannabinoid system is the one under duress during this hormone fluctuation.
Remember...estradiol's effect on mood is via FAAH and Anandamide (two endocannabinoids).
For more, check out CBD and stress here.
CBD and Neuroinflammation for Perimenopause Depression
This is the new frontier in mental health.
How the immune system can overreact and actually attack our neurons with results such as depression and anxiety.
The microglia, our brain's immune response cops figure strongly here:
Further studies revealed the activation of the brain immune cell microglia in depressed patients with a greater magnitude in individuals that committed suicide, indicating a crucial role for neuroinflammation in depression brain pathogenesis.
https://www.frontiersin.org/articles/10.3389/fncel.2015.00476/full
We just need to remember the connection between perimenopause and auto-immune disease risk.
Progesterone (along with Vitamin D - our steroid from the sun) is the master calming agent for immune response.
So...what about CBD there?
This might be its greatest effect...a positive shift in our immune response.
As for microglia:
Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer's disease.
https://www.ncbi.nlm.nih.gov/pubmed/21350020/
A state of "inflammation" or stress (immune system sees them in the same light) can have a long term depressive effect (Check out tryptophan, serotonin, and CBD).
Lipopolysaccharide induces “sickness behavior” in rodents, a syndrome that shows some similarity with depressive symptoms and depends on prolonged cytokines release and microglial activation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729885/
Lipopolysaccharide is the protein shell of bacteria that the microglia are on the lookout for.
Check out CBD and neuroinflammation for perimenopause depression to dive deep into this topic.
Finally, the mechanism by which estradiol affects mood...FAAH and Anandamide!
CBD for estrogen and perimenopause depression
A quick recap from above (it's a lot of information).
- Anandamide is our "bliss" molecule that occurs naturally in the brain.
- FAAH eats up anandamide
- Too much FAAH can mean depression, anxiety, and pain (see a woman who can't feel depression)
- Estradiol reduces FAAH (which boosts Anandamide).
So...what does CBD do for FAAH and Anandamide.
Jackpot!
In a study of CBD and schizophrenia (the most extreme example of imbalance), the results are powerful:
We further found that cannabidiol, at a concentration that reduces FAAH activity by ∼50%
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316151/
The resulting effect on anandamide was as expected:
Anandamide levels were higher in subjects exposed to cannabidiol than in those exposed to amisulpride
Amisulpride is an antipsychotic.
If you have a loved one who deals with schizophrenia, check out the CBD and schizophrenia here.
Immediately!!
The effects were via this increase on anandamide:
Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316151/
Just a head's up...in almost every study we've looked at, CBD and THC have opposite and opposing effects on given pathways.
Hormones are no exception:
Evidence suggests that marijuana can reduce female fertility by disrupting the hypothalamic release of gonadotropin-releasing hormone (GnRH), leading to reduced estrogen and progesterone production and anovulatory menstrual cycles.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918871/
Also, the effect on progesterone:
THC also inhibits steroidogenesis by preventing the conversion of pregnenolone to progesterone
https://www.zrtlab.com/blog/archive/the-effects-of-cannabis-on-your-hormones/
What else have we come across for perimenopause depression?
Other aids for perimenopause depression
Look, CBD is great to help support the pathways we discussed above but in the end, it's about hormones.
Estradiol and progesterone are critical players in your health, both mind and body.
We have a full review of estradiol supplementation and perimenopause here.
I was absolutely coming out of my skin until hormones started to be added back to the equation.
Progesterone (bio-identical) was a total game-changer.
Still is. Probably always will be.
We have a full review on progesterone but bioidentical is critical.
Remember...it goes first so as soon as you see fluctuation in periods, you're already getting low.
Late 30's, early '40s is when it starts to drop.
Some other key support items beyond hormones:
- Exercise (boosts BDNF)
- Mindful Meditation - see CBD, meditation, and exercise for neurogenesis
- Methylated B vitamins - especially if you're MTTR or MTHFR - get lab on how you're methylating
- Vitamin D - Almost everyone is low here (see the effect on serotonin here)
As for CBD, let's try to parse out how much.
How much CBD for perimenopause depression
We have better dosage research for anxiety but there is a shared component we can glean from that.
The neurogenesis (brain repair) piece!
It was found that the peak level of CBD for neurogenesis was 300mg.
That effect starts to decrease as we go past 300 mg as another pathway is triggered at higher levels.
Most people test 25-30 mg at first to see how their system responds.
Sleep studies point to 160mg as beneficial.
During the peak of perimenopause (I'm there now...month 4 with no period), I take 150 mg in the morning and 150 mg before bed.
I recently moved it to one dose after dinner for the evening.
This is because I take progesterone before bed (incredible for sleep) and CBD and progesterone both use liver pathways to process.
The CBD processing can actually reduce progesterone levels which I don't want (nor do you).
We want at least 2-4 hours separating the two.
I noticed that my progesterone was dropping (5000 to 3000) after heavy, concurrent CBD so they're separated out now and that's fine again.
Keep in mind that I have to take 300 mg of bioidentical progesterone just to get my levels up.
Everybody is different (as is every body).
This level of CBD brings up some key questions in terms of the type of CBD.
The best CBD for perimenopause depression
The basic requirements are true for perimenopause depression:
- Organically grown in the US
- CO2 extracted (cleanest option)
- 3rd party tested free of:
- No THC (check CBD to offset THC effects)
- No Heavy Metals
- No Pesticides
- No Bacteria
- No Mold
We actually test twice...after all, my entire family uses IndigoNaturals.
Two things pop up.
First, those are larger amounts of CBD for the peak neurogenesis effect.
We have to be able to afford this.
The cost per mg of CBD is the key consideration there.
We specifically price our 6000 mg bottles at 2-3 cents per mg before discounts for this reason.
Some of the lowest on the market as we want as many women as possible to avoid what I went through.
There's a lot of junk out there with 250 mg of CBD (if you're lucky) per bottle.
That's nothing...about 8 mg per dropper.
Secondly, full-spectrum versus CBD Isolate.
We only deal with isolate for two reasons.
First, all the research is on CBD by itself.
If it's not well-researched, we're not going there.
Maybe, more importantly, is the histamine issue.
All the plant material in full-spectrum is likely to hit histamine sufferers hard.
Does this matter for perimenopause?
In fact, the peak age for asthma exacerbations in women occurs at 50,10 which is also the mean age of menopause in the United States.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153393/
Peak age is 50??
That's also the height of perimenopause!
Go figure.
This speaks to the 40-60% of people with histamine issues, towards the higher end for women as they get older:
A large study of 1200 asthmatic women found that significant respiratory symptoms were nearly twice as common during the perimenopausal period, and FEV1 decreased by approximately 150 mL.
The last thing we want to do is take in a bunch of plant material while CBD shows powerful calming effects on histamine release (see CBD and histamines here).
Hopefully, we've introduced you to CBD and perimenopause depression.
Remember, it's a roller coaster with estradiol spiking and dropping.
Take care of yourself. Find ways to offset the swings and be well!
This glimpse into perimenopause is just the beginning. 'Dre's Story' offers our complete, research-rich journey into hormones, tools to feel better, and safety. The full Perimenopause Toolkit with new additions can be found Here. Please review so other can learn. Feeling better starts with understanding what is happening.
Get specific links for CBD and Perimenopause symptoms and questions here.
Let's help each other through this period.
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.