My lowest point as far as brain fog goes in a dreadful perimenopause journey (that story is here) was at a Safeway store.
I was trying to shop for groceries to have some sense of normalcy from 24/7 rolling panic attacks, disjointed sleep, and an almost complete shutdown.
I remember standing there in an aisle and just staring at a box of...I don't remember what.
Just staring at it.
The full story is here...brain fog was only part of it and 250,000 women in US will have a similarly brutal experience mid to late 40's.
After a while, I realized I was doing this and I really thought I was going into early-onset dementia.
That really helped the anxiety!
Ever since that experience, I've learned not to judge other people...you never know what's going on internally for them.
No one had warned me of perimenopause and what it can do to roughly 25% of women.
A total debilitating process.
Brain fog is front and center in this roller coaster to hell.
I found out the hard way after many failed medications and treatments how to navigate it better but I sure do wish someone could have tipped me off before...even mid 40's when progesterone was already starting to decline.
Let's look at brain fog from perimenopause.
We'll cover these topics:
- What causes perimenopause brain fog
- Perimenopausal oxidative stress and brain fog
- Brain fog and histamine response during perimenopause
- The endocannabinoid system and brain fog
- Can CBD help with perimenopause brain fog
- How much CBD to take for brain fog
- What's the CBD for perimenopause brain fog
Let's get into it.
Yes, it's okay to read it over twice. I've been there. You'll get out of it too.
What causes perimenopause brain fog?
First, you're not alone:
The Seattle Midlife Women’s Health Study reported that of 230 women aged 33 to 55 years who were interviewed about their perceived cognitive function, 60% noticed an unfavorable memory change “over the past few years”
First, a quick definition.
Brain fog is a nice umbrella term for a series of related effects:
- Inability to concentrate or focus (that Safeway store aisle)
- Can't think clearly.
We've all been there from a lack of sleep or following a hangover.
It's also very common around the period, during pregnancy, and our topic...perimenopause.
This is a huge clue assuming you're not staying up all night (not out of the question during perimenopause) or hungover (alcohol appears to the #1 "home remedy" for this transition).
Let's introduce estradiol!
It's our primary estrogen called E2 (out of 3).
Check out our complete review on estradiol and perimenopause to see just how important it is.
And not just for reproduction!
It's very frustrating and almost smacks of a conspiracy.
Our medical system focuses on hormones like estradiol and progesterone with a myopic lens on just reproduction.
It's so much more.
Since we're talking about brain fog, let's focus on estradiol's effect on cognition (the technical term for thinking).
If you're new to the whole perimenopause landscape, check out perimenopause versus menopause for a good introduction.
Ladies, we have to take care of each other.
Back to the brain!
During perimenopause (and monthly cycles and periods) there are abrupt fluctuations in estradiol.
First, understand that estradiol is our pro-growth hormone in the body and brain.
You could even call it excitatory like glutamate or choline (which we'll talk about later).
All are essential when our brains are running at full speed. You remember that feeling!
A good place to start is with studies that look at the cognitive effects when ovaries are removed (our primary source of estradiol).
For example, a study of rats after ovaries are removed (OVX) in a standard puzzle (water maze):
The results showed that the performance of OVX group in the water maze was significantly lower than the control group.
They go on to say...
This finding provides further evidence for the role of estrogen, a gonadal steroid hormone, in the manipulation of functions related to learning and memory
And when the replaced estrogen in rats with ovaries removed:
Using different behavioral paradigms in rodents, estrogen replacement was shown to enhance learning and memory as well as attenuate learning deficits associated with cholinergic impairment.
That's our first clue...cholinergic. That's short for choline.
What does choline do in the brain?
Here's where it gets interesting.
Choline does many things but the big one is converting to acetylcholine.
So...what does acetylcholine do?
In the central nervous system, ACh has a variety of effects on plasticity, arousal, and reward. ACh has an important role in the enhancement of alertness when we wake up, in sustaining attention  and in learning and memory.
That sounds important for brain fog. We did a huge review on acetylcholine since we can supplement for it.
Any relationship to estradiol...you know...the hormone only used for making babies?
17-β estradiol is able to modulate the AChE activity and non-neuronal cholinergic response as well as to reduce lipid peroxidation.
Ladies, we could literally drop mic and walk off the stage there.
In fact, they found all these complicated effects by looking at what happens when ovaries are removed (very quick perimenopause if you will).
To wrap it all up in a bow:
By genomic and non-genomic pathways, estrogens elevate levels of neurotransmitters such as serotonin and acetylcholine, promote neuronal growth and formation of synapses, act as antioxidants and have regulatory effects on calcium homeostasis and second messenger systems
Ladies, this stuff is important!
Estradiol boosts choline levels and estradiol is spiking and dropping during perimenopause.
We'll get into what we can do about it below.
Look...there's a huge tie between acetylcholine and dementia as a woman are disproportionately hit by these brain-wasting diseases Check out CBD and dementia.
Loss of p75NTR receptors that are modulated by estrogen (Bora et al., 2005) on basal forebrain cholinergic neurons is associated with early evidence of cognitive dysfunction even without evidence of cellular loss
Is there any wonder why after what we just saw with estradiol???
Has research seen the effect of hormone replacement and Alzheimer's?
Risk varied with duration of HRT use so that a woman's sex-specific increase in risk disappeared entirely with more than 10 years of treatment
The trick is that you have to support these systems (estradiol and acetylcholine) early on!
There's a window for hormone replacement to negate cognitive decline, after which, it has less effect.
We'll get into a side-wrinkle on that whole equation below in the endocannabinoid system section.
That was the real message from the scary 2001 WHI study that freaked many women out.
Women who started hormone replacement at an older age didn't see the benefits.
Again, there may be a way to offset that effect which we'll see below.
That's the choline pathway that estradiol directly boosts and controls.
There's another key aspect to look at which we can definitely affect.
Perimenopausal oxidative stress and brain fog
Brain fog comes up in another situation aside from perimenopause which sheds some light on its cause as well.
Radiation and chemo treatment for cancer.
To understand why we have to get to the root of how these treatments work.
Essentially, they create massive amounts of oxidative stress within cells that kill them.
This mirrors our own body's mechanism to get rid of cells naturally.
In fact, you have an entire system that looks for broken (senescent) and pre-cancerous cells.
When it detects such a cell, it ramps up oxidation and kills it.
Assuming the system is working correctly!
They call this result of treatment "chemo brain".
For example, in one study, they administered a common chemo drug to mice (Dox) which resulted in intense oxidation and cognitive decline.
They then administered a powerful anti-oxidant (MESNA) to one group of the mice.
Using novel object recognition (NOR), we demonstrated the Dox administration resulted in memory deficits, an effect that was rescued by MESNA.
And what was the pathway by which this all occurred?
Can you guess it??
Using hydrogen magnetic resonance imaging spectroscopy (H1-MRS) techniques, we demonstrated that Dox administration led to a dramatic decrease in choline-containing compounds assessed by (Cho)/creatine ratios in the hippocampus in mice.
Choline. The precursor to acetylcholine we spent so much time on above.
An important note on that result. The hippocampus.
It's just the seat of memory (standing in Safeway with none of it).
What does estradiol (just for making babies) do there?
We'll combine two important pieces:
- The effect for estrogens in our environment (such as BPA from plastic)
- Estradiols effect in the hippocampus
Here it is:
Our data indicate that even at this relatively low exposure level, BPA completely abolishes the synaptogenic response to estradiol.
This is just the tip of the xenoestrogen iceberg (estrogen interrupting chemicals in our environment).
- Canned foods. Metal (aluminum) food and drink cans are commonly coated with BPA-containing epoxy films. ...
- Reusable water bottles (Polycarbonate plastic #7). ...
- Soda and beer (in cans). ...
- Fast food containers (that waxy cup or container). ...
- Cash register receipts.
Let's go back through that first piece.
Levels that the FDA considers safe can totally block estradiol's natural ability to build new connections in the hippocampus.
Just a head's up...the hippocampus is our most dynamic part of the brain.
You can't add new memories without adding new synapses.
Apparently, you can't do this with "safe" levels of BPA!
We'll add that to the list (glyphosate, PFOA, and 10's of thousands of others) on why there may be more autism, more dementia, and earlier perimenopause.
We'll look at how CBD affects hippocampus neurogenesis below.
Back to inflammation.
We see this effect with obesity as well which creates a widespread systemic inflammation.
Weight gain is a key complaint during perimenopause.
Remember that fat cells can make estradiol and the body panics from the loss of ovarian-produced estradiol.
Remember...it's not JUST for reproduction...
Look what happens when they block estrogen receptors in terms of fat and metabolism:
Female and male mice that lack ERα have central obesity, have severe insulin resistance and are diabetic
That link has dozens of pathways showing how estradiol offsets obesity and the inflammation that results from it.
We did a big review of CBD and perimenopause weight gain.
We'll look at how to reduce oxidation (chemo brain) and inflammation below.
Speaking of inflammation, let's check out histamine and brain fog.
Brain fog and histamine response during perimenopause
If you've ever had really bad allergies, you'll understand this effect.
Histamines (or mast cell release) and brain fog.
In fact, if you look at people with severe histamine response, the brain fog association is telling:
Brain “fog” is particularly common in patients with systemic mastocytosis (SM) (Theoharides et al., 2015c) or disorders of mast cell (MC) activation
How bad can it be??
A recent survey of the symptoms experienced by patients with MC disorders reported that >90% of them experienced moderate to severe brain “fog” almost daily (Moura et al., 2012) and cognitive impairment was confirmed using a validated instrument
Mast cells are where histamine (the chemical behind allergy responses) is stored.
Hormones like estrogen and progesterone directly affect this pathway:
Finally, 30–40% of the women with asthma have perimenstrual worsening during phases of rapid changes in estrogen and progesterone concentrations
Rapid change is definitely a characteristic of perimenopause (see perimenopause versus menopause).
One note on this.
Estradiol is pro-growth, excitatory in nature. Histamine is excitatory in nature
Progesterone is calming and inhibitory in nature.
Progesterone supplementation may be key here to calm the allergic drive of estradiol.
In contrast, progesterone (100 pM to 100 nM) had a significant inhibitory effect on histamine secretion induced by IgE-DNP in PMCs from both male and female rats
Interestingly, the needed progesterone to elicit this effect was 1000 times higher for men than women.
Remember that progesterone starts to drop late 30's, early 40's.
Allergies are highest for women and increase as they get older.
We'll look at how to address that below.
Let's take a quick detour to the endocannabinoid system before jumping into CBD.
The endocannabinoid system and brain fog
We all have one.
It's a check and balance system tasked with homeostasis (balance) for other key systems:
- Nervous system including serotonin, BDNF, acetylcholine, and peptides neurokinin B
- Immune system - inflammatory responders
- Endocrine system - Hormone!!!
So...maybe this is important for perimenopause brain fog.
These systems are crazy complicated so let's tease out some key examples.
We'll start with our favorite.
Anandamide is a naturally occurring endocannabinoid in your brain right now (hopefully)!
It's called the "bliss" molecule and named after Anand, the Hindu goddess of bliss.
Its effects are all over aspects of brain function.
What about acetylcholine which seems to be the linchpin for brain fog.
Anandamide increased both basal [3H]-acetylcholine release (pEC(50) 6.3) and muscle tone (pEC(50) 6.3).
In other situations, it reduces it.
In that same study, they showed interaction with neurokinin B and the other tachykinins.
As for oxidation and inflammation, this may be the endocannabinoid system's wheelhouse.
Remember how chemo increases cellular oxidation and brain fog (chemo brain) is a common effect of this?
Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level.
Wait till you see what CBD does there below. Very exciting.
Then there's the seat of memory...the hippocampus.
Neurogenesis or the repair/growth of neurons in this area is key!
What system in the body is in charge of neuron birth and death?
On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis.
Finally and this is very interesting for hormone replacement.
The 2002 WHI study showed that women who started hormone replacement later (after menopause started) missed out on the benefits.
Recent studies have shown that the endocannabinoid system may help to extend or re-open this window!
This is brand new research (2019).
It appears to center around our brain's most powerful endocannabinoid, 2AG:
Blood samples from postmenopausal women aged 56–65 indicated decreases of miR-221-5p and 2-arachidonoylglycerol compared with samples from perimenopausal women aged 46–55.
They then found they could reverse this by stimulating CB1 (receptor):
The present study demonstrates that an HT time window in mice can be prolonged by cotreatment with a CB1 agonist, implying a potential strategy for HT in long-term menopausal women.
HT is short for hormone therapy...replacement essentially.
Anandamide is our most potent CB1 agonist and CBD has a direct effect there which we'll look at next.
Okay okay. Enough. Let's see what we can do about these pathways for perimenopause brain fog.
While we can still focus on the words!
Can CBD help with perimenopause brain fog
First, understand that aids like CBD are helpful but if your hormones are depleted, it's fiddling while Rome burns (Rome being your brain).
- Estradiol for perimenopause
- Siberian Rhubarb review (alternative and protective for estradiol activity) Buy Here
- Pregnenolone - a precursor to progesterone Buy Here
All are available here.
We'll look at CBD on these pathways:
- CBD for acetylcholine levels key to perimenopause brain fog
- CBD and brain oxidation for perimenopause brain fog
- CBD and brain inflammation for perimenopause brain fog
- CBD and hippocampus neurogenesis for perimenopause brain fog
Let's get started.
We'll also look at other things we've come across that can help.
Hey, we would have loved this information prior to the Safeway debacle.
CBD for acetylcholine levels key to perimenopause brain fog
We've seen how choline and its direct metabolite, acetylcholine are key to cognitive functioning.
Estradiol directly drives its levels.
Anandamide also drives its levels as we saw above.
Can CBD affect this pathway?
First, it's been known for a while that CBD has a wake-promotion function.
That's the alertness and focus effect.
Interestingly, it also helps with sleep so clearly its effect (owing to the balanced nature of the endocannabinoid system it supports) is dependent on where you are in the 24-hour cycle.
A similar effect on sleep was observed when CBD was injected into the lateral hypothalamus  suggesting that CBD behaves as a wake-promoting compound.
Acetylcholine (and cortisol/histamine) figure into wake-promoting effects.
Does CBD affect acetylcholine directly?
Here, we demonstrate that systemic injections of CBD (0, 5, 10 or 30 mg/kg, i.p.) at the beginning of the lights-on period, increase the extracellular levels of ACh collected from the basal forebrain and measured by microdialysis and HPLC means
Awesome! Notice the "lights-on" part? We don't this in the middle of the night (see CBD and perimenopause sleep).
What about Anandamide which is part of our own internal control for acetylcholine?
Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
That study on CBD's effects on schizophrenia (a ridiculously complicated disease in terms of brain activity) should be required reading.
Check out CBD and schizophrenia here.
For choline support, here are some other tips:
Eggs!! A huge source of choline and new studies are showing that the plaque in arteries actually has the genetic signature of bacteria (from the mouth), not from liver or food.
- Choline CDP (buy here)
- Mindful Meditation (Check out CBD, exercise, and mindful medication here)
Next up...reducing oxidation.
CBD and brain oxidation for perimenopause brain fog
We've written extensively on this since oxidation may be at the heart of many mental health issues such as anxiety and depression (both very common in perimenopause).
CBD is a powerful antioxidant
In fact, it laps both Vitamin E and C:
Although all of the antioxidants attenuated glutamate toxicity, cannabidiol was significantly more protective than either α-tocopherol or ascorbate.
Check out CBD and oxidation stress here.
What about glutathione, our workhorse anti-oxidant?
Remember that chemo agent, DOX which causes rapid oxidation and resulting cognitive decline?
Its effects are as intended (for the cancer cells and healthy cells alike):
DOX’s cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death.
What happened when they supplemented CBD?
Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis.
The most exciting part of that study is this.
CBD has different effects depending on the state of the cell:
- Non stressed cellular environment - no effect
- Stress cellular environment - reduces oxidative stress
- Precancerous or cancerous cell - increases oxidation
Read that back over. It's probably the most impressive example of how the underlying endocannabinoid system works.
Check out CBD and glutathione for more.
CBD and brain inflammation for perimenopause brain fog
Then there's brain inflammation.
Keep in mind that both estradiol and progesterone are anti-inflammatory and neuroprotective (plus, they make babies).
Look...much of the ravages of age come down to our brain's immune system going haywire.
The whole umbrella of "autoimmune" disease fall under this category and women make up 80% of diagnosis...many of which spike after perimenopause.
Add dementia and Alzheimer's to that list.
Why would a loss of estradiol and progesterone have this result?
Microglia are the brain's immune police.
Estradiol's effect there?
With regard to microglia, in recent years our studies showed a major anti-inflammatory activity of estradiol in microglia activated by strong inflammatory stimuli such as lipopolysaccharide
Can CBD take some of the load off of estradiol's effect there?
Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer's disease.
Ladies...this is an insurance policy against dementia and Alzheimer's.
All the current research is pointing this way in terms of immune overreaction.
Check out CBD and microglia here.
That's the damaging side (which unrestrained microglia do).
- Curcumin - powerful anti-inflammatory
- Vitamin C
What about the repair side?
CBD and hippocampus neurogenesis for perimenopause brain fog
This may be our favorite piece.
We've covered it quite a bit here:
- CBD and hippocampus neurogenesis
- CBD and elderly anxiety
- CBD, exercise, and mediation of brain repair
We'll focus on:
- hippocampus (memory and learning)
- prefrontal cortex (higher executive function - thinking!!)
One (of many) examples shows the restorative effect of CBD on hippocampus volume for heavy THC users:
These findings suggest a regionally specific restorative effect of CBD upon the subicular and CA1 subfields for heavy cannabis users.
Don't get us started on the CBD versus THC.
What does the CA1 area of the hippocampus do?
Functionally, CA1 neurons are critically involved in the representation of temporal and spatial contextual information and retrieval of episodic memory
That might be important for perimenopausal brain fog.
What about the other key area for thinking...the prefrontal cortex?
Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex.
We covered this in-depth at our CBD for perimenopause depression.
We'll end with it here because it covers so many bases.
- BDNF - our brain's fertilizer
- Synaptogenesis - repairing and building new brain pathways
- Prefrontal cortex - the part of the brain that separates us from animals
On to some practical questions.
How much CBD for perimenopause brain fog
This is really going to depend on your situation.
We have some guidance at our how much CBD article but there is one clue.
The neurogenesis effect appears to peak in research at about 300 mg.
Above that, a different pathway kicks in.
People generally start much lower to see how they respond at about 25-30mg.
At the 1000mg bottle, that's a little less than one full dropper.
CBD definitely helps me during this period but hormones must be addressed even if it's via Siberian Rhubarb (full review here).
Cognitive issues are one of the main symptoms listed in the Menopause Related Symptoms that it helps to address.
Of course, our full review on estradiol for perimenopause is here.
Next up...the best type of CBD.
What's the best type of CBD for perimenopause brain fog
There's a lot of junk out there.
First, the following are mandatory:
- Organically grown in the US on an FDA registered farm
- 3rd party tested with posted Certificates of Analysis (see ours here)
- No THC - see why CBD is a must against THC
- No pesticides - Glyphosate actually blocks steroidal hormones at the top with pregnenolone
- No mold
- No bacteria
- No heavy metals
We actually test twice at IndigoNaturals (biomass and finished product) since our entire family uses the product.
One last piece that's very important.
Most of the market is pushing full-spectrum as better.
Better for whom?
First, check out CBD isolate versus full spectrum for a good review of this whole comparison.
Finally, the histamine issue.
There's a lot of plant material in full-spectrum.
Roughly 40-60% of people have histamine issues and women are at the top range as they get older!
We talked about histamine and brain fog above (think allergy attack).
It appears that some histamine is necessary for alertness, learning, and motivation, but too much histamine shuts the system down, in MCs and histaminergic neurons, by activating H3 autoinhibitory receptors leading to brain “fog” (Table
We want clean CBD isolate which is why we only add MCT oil (a coconut oil extract).
All plant material is likely to send women in perimenopause the wrong direction and we get messages to that effect all the time.
Remember choline. Exercise and meditate. CBD to help smooth out the inflammation. Look at hormones!
Be well ladies. We have to look after each other!
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.
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.