Pregnenolone - Guide for Health, Perimenopause, and Aging

 
It's been a long and winding road to bring us here.

If you've ever had a serious health issue and the standard medical practice sent you in a tailspin, you'll understand.

The combination of a severe perimenopause - oral typhoid vaccine serum sickness was my 1-2 punch.

I was spiraling in 24/7 panic attacks, rolling blood pressure and heart rate spikes.

Then came the medications - benzos, SSRIs, blood pressure meds, heart medications.

I almost didn't make it out.  That story is here.

Finally, I started to get some relief from CBD, progesterone, and estradiol after about 5 doctors, months of torture, a psychotic break from medication interactions, and diving deep into the research.

 

The hormones and CBD really helped but I always had a feeling from the hormones that they weren't "mine".

It just wasn't right.

Listen...I was 90% better than the low point (3 nights of zero sleep landing me in an ER) but some things lingered.

 

I had intense nerve pain in my heels (yes...just my feet). 

I could barely walk.

Yes, I had seen about 4 foot doctors, acupuncturists, and chiropractors by then!

We had the boot (ruined my other foot), arch supports, x-rays, MRI's, socks, icing, heat….you name it.

It was so depressing not to be able to walk!!

I also still had these shots of adrenaline or cortisol at about 4 am.

My heart would race and I would slowly get back to sleep with CBD and magnesium glycinate.

See our article on CBD and sleep. 

Occasional anxiety and negative thoughts still would crop up at night.

These things lingered for a year or so after things started to get back to normal.

 

I can't explain the breadth and depth of my research to get to the bottom of this.

• Genetics.  Check
• Gut biome.  Check
• Histamine response and diet.  Check
• Supplements for every possible deficiency. 
• Naturopaths.  Mds.  Specialists.
• Bioidentical hormones.  Yes.

 

Check out our CBD and Anxiety page as just a smattering of our research.

CBD was a lifesaver but I still had those lingering issues.

Back to the research.

I had come across pregnenolone a few times but didn't pay much attention to it.

After all, I'm already on progesterone, estradiol, testosterone, and actually using the Dutch test to monitor how my body metabolizes them.

What about pregnenolone?

Joe from Selfhacked said it's one of his favorite nutraceuticals.  Suzanne Somers swore by it in her book, I'm Too Young For This.

 

But I had the whole hormone thing covered!

Or did I??

Two interesting articles popped up.

One showed that people's cholesterol levels can elevate as the brain tries to compensate for the loss in pregnenolone.  

 

Hmmm...that tracked my trajectory.

We tend to lose about 70% of our pregnenolone by age 70.

Another clue!

We come across a lot of references on THC while researching CBD.

Another study showed that pregnenolone is the reason that it's so hard to overdose on THC.

THC causes a protective spike in pregnenolone to protect the brain and nervous system.

Finally, pregnenolone was shown to be the mother of all hormones!

See our article on CBD and perimenopause depression. 

My sleep is better and I don't have that the shock in the middle of the night or wake up with the vision flurries.

Negative thoughts are...gone.

I still take the CBD and supplements but I'm going to seriously look at the hormone piece.

I'll explain why below.

Buckle your belts...we're going deep into pregnenolone, how it works, and why it might just save millions of people from suffering.

Of course, we're going to rely heavily on NIH research.

It's actually lacking compared to other substances but as one article said...you can't patent and profit off of pregnenolone (see more on the new allopregnanolone drug for postpartum depression at $25K a pop below).

We'll cover these topics:

• What exactly is pregnenolone
• Pregnenolone is the mother of hormones
• Relationship between pregnenolone and cholesterol
• Does pregnenolone increase cortisol, estrogen, progesterone, or testosterone
• Pregnenolone levels by age and gender
• Pregnenolone and the endocannabinoid system
• Benefits of health pregnenolone levels
• The pregnenolone and DHEA warning
• Allopregnanolone and pregnenolone for postpartum depression
• Adrenal fatigue and pregnenolone
• What CBD and Pregnenolone have in common
• Best time of day to take pregnenolone
• Can you test for pregnenolone levels
• Best pregnenolone
• Do I need a prescription for pregnenolone 

Like we said, we're not messing around.

We were originally surprised at the sheer lack of coverage and information on pregnenolone which is partially why we waited so long to try it.

All that wasted time!

What exactly is pregnenolone

This is part of the initial confusion.

• Is it a steroid?
• Is it a hormone?
• Is it an endocannabinoid?

 

Why then it is treated like a food supplement by the FDA?

You can buy it at grocery or vitamin stores anywhere.  We found good pricing here.

 

Here's where it gets interesting. 

Technically, pregnenolone has the chemical structure of a steroid, acts as a precursor "raw material" for all sex hormones, and is also an endocannabinoid.

Goodness...that's a lot to carry!

The term "steroid" has a scary connotation but it just means a substance that is a type of fat (lipid) that doesn't mix with water.

The "steroids" most people think of are very high levels for the body compared to where pregnenolone functions.

Most people don't realize that cholesterol is our most common steroid!

In general, steroids are "excitatory" in some parts of the body or brain.

They spur activity along certain pathways.

Research is actually pointing to pregnenolone as more of a "raw material" for the other naturally occurring steroids in the brain:

Looking at the whole picture of steroids, PREG is often known as the precursor to other steroids and not as an active steroid per se.

https://www.ncbi.nlm.nih.gov/pubmed/26433186

So precursor to all hormones.  The precursor to steroids.

Clearly, this is a very interesting substance.

Most importantly, its levels start dropping in the early '30s (see levels by age and gender below).

We'll get into some of its researched effects below.

Pregnenolone can also be metabolized into Pregnenolone Sulfate which has its own interesting characteristics.

Its effects on neurotransmitters are far and wide:

Pregnenolone sulfate also has significant regulatory effects on the release of many important neurotransmitters, such as glutamate, GABA, acetylcholine, norepinephrine, and dopamine. 

https://www.sciencedirect.com/topics/medicine-and-dentistry/pregnenolone-sulfate

We've covered GABA quite a bit for anxiety (see CBD and GABA) but GABA and glutamate alone are the brain's primary gas and a brake pedal.  

Incredibly important and powerful.

The keyword there is "regulatory".  Not boosting or reducing but balancing.

That brings us to our real identity under the steroid and hormone disguises.

Finally...pregnenolone as an endocannabinoid.

This is where it gets interesting.

Pregnenolone can directly affect the CB1 (endocannabinoid) receptors:

Pregnenolone is an allosteric endocannabinoid, as it is a negative allosteric modulator of the CB1 receptor.

https://www.sciencedirect.com/science/article/pii/S0960076015300893?via%3Dihub

Only endocannabinoids can do this!  To translate!!

Pregnenolone sets a ceiling on endocannabinoid activity.  CBD sets a bottom (allosteric postive modulator).

This throws an entirely different spin on the whole idea of what pregnenolone really is!

We're going to jump into this further but it also speaks to the strong safety profile of pregnenolone as opposed to true steroids and hormones.

 

The endocannabinoid system is a regulatory system.  A system of checks and balances.

We went deep into how this system may be the key to modern disease.

We'll get into what that really means below but it's a fascinating system and one we know well from our studies on CBD.

CBD, which bolsters the endocannabinoid system has been shown to have powerful effects on balancing hormone levels.

 

We may finally know by what mechanism.

Let's look at each of these roles in more detail.

Pregnenolone is the mother of hormones

This really is pregnenolone's starring role.

It's the precursor to ALL our sex or steroidal hormones.

Not just progesterone.  Not just testosterone or estrogen. 

All of them!

There are over 200 hormone and hormone-like substances in the brain and body.

We have hormones that govern everything from hunger, to stress response, to sex drive, to mood, to blood pressure!

 

It's called the endocrine system.

Most people don't realize how powerful and far-reaching this system is.

The so-called "sex" hormones are incredibly powerful beyond procreation.

They ALL originate from one source.

Pregnenolone.

From this one substance, there's a cascade of different pathways to these various hormones.

Some are direct while others have to go through a series of chemical changes.

There's an interesting summary of common pathways for the steroid hormones here:

https://www.gdx.net/files/clinicians/medical-education/previous-webinars/June-2016-The-Steroidogenic-Pathway-Understanding-What-Influences-Each-Step-Antoine.pdf

It's best to think of pregnenolone like protein (for muscle) or calcium (for bones).

But for hormones!

Look...hormones are complicated and it's easy to fall down the rabbit's hole on this.

They are highly involved in almost every aspect of our health and functioning.  

Here's what relevant for us.

The levels of pregnenolone and mitochondria activity (where cholesterol is converted to pregnenolone) drops as we get older.

Correspondingly and expected, all our core hormones also drop as we get older.

People tend to think of these as "sex hormones" that govern libido and pregnancy but that's just one tiny aspect of what they do.

For example, one of the main hormone transformations from pregnenolone is progesterone.

Yes, progesterone is key to a woman's monthly cycle but it's integral to many other systems.

Just some highlights:

• Boost mood
• Boost energy
• Improves sleep
• Builds bone and muscles
• Protects against cancer

https://www.larabriden.com/superpowers-benefits-progesterone/

Those are just highlights (but she has a great article on why bioidentical is so much better than synthetic (progesterone versus progestin) here.

 

We have a deep dive on progesterone, estrogen, and testosterone is coming soon.

Progesterone is a key precursor to other steroid hormones, including cortisol, testosterone, and estrogens (estriol, estradiol, and estrone).

That's just one by-product of pregnenolone and we could fill an entire article.

The key issue I originally had was this…

I'm already supplementing with progesterone and estradiol.

They had a hugely positive (transformative really)  impact on anxiety, mood, sleep, etc as I mentioned above.

I was leary in adding pregnenolone because there was information online about increasing cortisol which appeared to be in ample supply in my system (nighttime cortisol shots).

Turns out it's more nuanced than that.

In fact, each end-result hormone has its own originating cell type and specific enzymes:

This leads many to incorrectly assume there is a single "pool" of pregnenolone available for all steroid hormone synthesis within the adrenal.

https://www.zrtlab.com/blog/archive/reassessing-pregnenolone-steal/

This speaks to the whole "pregnenolone steal" theory where some sites posit that the body "steals" available pools of pregnenolone to make cortisol from other hormones (progesterone primarily).

That same article talks about the importance of stress and inflammatory signals that govern how pregnenolone is converted into other key hormones such as DHEA.

Our focus is on how pregnenolone levels decrease as we get older.

One of the first clues came from the relationship between increasing cholesterol levels and pregnenolone.

Relationship between pregnenolone and cholesterol

This was the first study that peaked our curiosity.

It's pretty amazing!

Basically, researchers were curious if natural drops in hormones (see pregnenolone levels by age and gender below) could explain the gradual rise in cholesterol levels.

Their results:

The astounding result from this study was that by properly replacing the steroidal hormones lost to normal aging, 100% of the subjects experienced a significant reduction in blood cholesterol levels.

https://www.lifeextension.com/magazine/2003/9/report_chol/Page-01

The actual study is here where they dropped cholesterol from 228 to 183 with just hormone replacement (HT):

HT lowered mean TC from 228.8 mg/dL to 183.7 mg/dL (19.7%) (p<0.05) in all patients.

https://www.ncbi.nlm.nih.gov/pubmed/21407165

Think about that...they dropped cholesterol levels by supporting steroidal hormones.

The theory is that the body is trying to compensate for reduced hormones (which are critical to so many aspects of health) by increasing its raw material...cholesterol.

Cholesterol is the source material for pregnenolone which then gets converted into ALL steroidal hormones.

Just a quick news flash...we have millions of people on statins which reduce cholesterol levels.

The so-called "bad cholesterol" - LDL is the primary source of pregnenolone and we're directly driving it down.

 

Read up on the studies of cholesterol and heart disease.

It's fascinating in light of new research (inflammation and bacterial lipid production).

We do know that cholesterol levels generally increase as we get older.

Based on what we just looked at, it's a perfect time to jump into pregnenolone levels by age.

Pregnenolone levels by age and gender

The Chinese have a saying:

Hao de kai shi jiu shi cheng gong de yi ban

Well begun is half done.

The opposite is true for pregnenolone's naming.

It doesn't exactly roll off the tongue and if you're like us, you have to use the first four letters of "pregnant" to cue the memory.

That immediately conjures up a gender bias for pregnenolone.

People assume that it's a sex hormone-like estrogen or testosterone which scares most people away.

The actual status is quite different!

Keep in mind that the "androgens" or sex hormones like estrogen, testosterone, progesterone, and others, only make up a small fraction of our total hormone family.

By the age of 75, our bodies produce 60% less pregnenolone than the levels produced in our mid-thirties.3 For this reason, pregnenolone is one of the biomarkers of aging.

https://www.grc.com/health/research/Pregnenolone/Pregnenolone_Review.pdf

Quite poignantly put:

Like counting the rings of a tree, by measuring the level of pregnenolone at any given point of a person's life, it is often possible to make an educated guess as to his or her age. 

 

DHEA (a derivative hormone from pregnenolone) is an established biomarker for aging in all primates:

From the early thirties on, there is a steady decline (about 2% each year) until around age 75, when the level of DHEA in the body is about 5% of the peak level. Because DHEA-S is related to age and longevity 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938178/

Furthermore, calorie restriction, which is known to slow aging also showed it's effect in maintaining DHEA levels: 

Most important is the finding that, in rhesus monkeys, calorie restriction, which extends life span and retards aging in laboratory rodents, slows the postmaturational decline in serum DHEAS levels.

https://www.ncbi.nlm.nih.gov/pubmed/9215277/

Here was another big clue for us...the levels of pregnenolone are about equal for men and women...throughout their lifetimes!

Every other hormone has significant differences in steroidal hormone levels (both across lifespan and within cycles) between genders.

The only difference is that the levels drop as we age.

That should be a huge warning bell.

Pregnenolone peaks about age 20 and declines by about 70% by the age of 70.

A good NIH review of pregnenolone levels can be found here: 

https://www.ncbi.nlm.nih.gov/pubmed/6308031

This matches subsequent drops in key hormones across the body and brain.

Unfortunately, it mirrors a host of health and mental markers of decline.

If a 20-year-old (male or female) has peak levels of about 200 mg and a 70-year-old has about 50 mg, isn't that a big wake up call for longevity?

 

Ask a standard medical doctor and they won't bat an eye at it.

"Those levels are normal for your age".

Normal??

Why wouldn't I want the 20-year-old's level at 50?  (I'm only 49 by the way).

Given the power of hormones we discussed above,  it's incredulous that we just sit back and watch key levels drop.

It starts with pregnenolone.

Actually, it really starts with cholesterol!

Yes, the bad guy in our healthcare system.  The medical boogeyman.

By the way...dig a little deeper into the story spun for cholesterol-reducing medicines (billion dollar market by the way).

 

Recent studies using cutting edge scanning technology point to the plaque being lined in arteries as genetically not coming from us (our liver) or what we eat.

They have the telltale signs of bacteria!

Yes...bacteria waste (as lipids) from mouth bacteria and others that can jump gut and other barriers.

https://www.sciencedaily.com/releases/2017/11/171101151213.htm

We won't rock that billion-dollar boat though.

We've heard before that cholesterol is brain food but we didn't really know the exact mechanism.

Here's the sausage-making.

Cholesterol in the brain is turned into pregnenolone via a gene called StAR.

That's the ONLY source of pregnenolone (outside of supplementing).

By the way, Glyphosate (chemical in RoundUp and 90% of corn, wheat, and soy production in the US), directly impedes the StAR gene activity pregnenolone!

 

It's not just Glyphosate as many pesticides upset this process.

In terms of aging, the relationship between mitochondria (our cell's power plants) and pregnenolone is interesting:

Decline in sex steroid hormones and accumulation of mitochondrial damage may create a positive feedback loop that contributes to the progressive degeneration in tissue function during aging.

 

Remember that StAR gene activity which converts cholesterol to pregnenolone?

It occurs in the mitochondria. (see CBD and mitochondria).

The mitochondria may be the weak link for our bodies in terms of aging.

There's a very detailed study of the effects of steroidal hormones upon mitochondria:

Conversely, sex steroid hormones help to maintain mitochondrial function and limit aging phenotypes

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922316/

Does pregnenolone increase cortisol, estrogen, progesterone, or testosterone?

My original concern with taking pregnenolone was that I didn't want more cortisol.

That brings up the question...does supplementing pregnenolone increase other hormones more than you want or need?

This is where it gets very interesting.

First, we need studies that directly study these interactions.

The best study we have is one where pregnenolone significantly improved results for patients with schizophrenia:

Treatment with pregnenolone did not increase serum testosterone, free testosterone, cortisol, DHEA, estradiol, or androstenedione levels

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427920/

So….that's cortisol, testosterone, estradiol (one of the three estrogens).

Cortisol (our stress hormone - see CBD and cortisol for anxiety) actually dropped a bit which points to pregnenolone's effect on the stress response.

There was, however a big effect on other key hormones: 

Treatment with pregnenolone resulted in fourfold elevations in serum levels of pregnenolone (paired t-test p = 0.017, t = 3.11, df = 7), tripled serum pregnenolone sulfate levels (paired t-test p <0.0001, t = 10.44, df = 8), and increased the GABAergic neurosteroid allopregnanolone fivefold

 

Allopregnanolone and Progesterone both went up significantly!

Allopregnanolone is the basis for the new postpartum depression medication that's selling for $25K and requires 2 days in the hospital.

 

You do the math!

It actually makes us angry.  

In the 8 week study, allopregnanolone went up 8 fold from pregnenolone!

Pregnenolone costs about $12 per bottle here.  It's also not synthetic which is critical because every instance we've seen of synthetic hormones has been bad (see progestin versus progesterone as just one example).

 

The same is true for cannabinoids!

The interesting point is this...pregnenolone did not increase all hormones (that originate from it) equally.

Very fascinating.

The reason I held off was because I didn't want an increase in cortisol.

In the study, cortisol actually went down a bit.

We'll try to touch on why this is in the endocannabinoid section below.

Pregnenolone levels by age and gender

As we mentioned above, our pregnenolone levels drop as we get older.

This means all our hormone levels have to drop as well since they ultimately derive from pregnenolone.

There's even a difference between men and women which may speak to some of the key gender differences (autoimmune, anxiety/depression, Alzheimer's/Dementia, etc):

Pregnenolone sulfate levels in women reached their maximum at about age 32 yr and then declined continuously, and in males, the maximum was reached about 5 yr earlier and then remained nearly constant. 

https://www.ncbi.nlm.nih.gov/pubmed/11994368

As for "normal" levels:

• Normal circulating levels of pregnenolone are as follows:[15]
• Men: 10 to 200 ng/dL
• Women: 10 to 230 ng/dL
• Children: 10 to 48 ng/dL
• Adolescent boys: 10 to 50 ng/dL
• Adolescent girls: 15 to 84 ng/dL

https://en.wikipedia.org/wiki/Pregnenolone

Here's our favorite part:

Mean levels of pregnenolone have been found not to significantly differ in postmenopausal women and elderly men (40 and 39 ng/dL, respectively)

 

So...a drop of the mother of all steroidal hormones from roughly 200 to 40 ng/dl as we age...

Why is this just "accepted"?

You're done having babies...out to pasture for you!

We mentioned above that researchers can estimate age pretty well by seeing levels of pregnenolone.

Pregnenolone and one of its byproducts (DHEA) are both known biomarkers for aging.

They decrease as we get older.

Of course, there's a corresponding drop in all the downstream hormones as well.

Let's now jump to the fascinating aspect of pregnenolone...its effect on the endocannabinoid system.

Pregnenolone and the endocannabinoid system

In the study above on schizophrenia, why did pregnenolone boost progesterone and allopregnanolone but not some other downstream metabolites like cortisol or testosterone?

What are the constraints in the body that decide what gets made from this raw material?

In fact, there's a host of signals both internal and external that dictate the pathways to all our steroid hormones.

The fact that pregnenolone directly affects endocannabinoid receptors (CB1 to be exact) points to an interesting intersection.

In all our articles (dozens now) on CBD, we give a quick introduction to the endocannabinoid system.

Research generally shows that this system helps to balance other key systems:

• Nervous system - neurotransmitters like serotonin, GABA, dopamine, and others
• Immune system - inflammatory agents like cytokines, microglia, and the gut biome
• Endocrine system - hormones!!

 

The issue is that our hormone system is so complicated and interwoven with other players in the body, we'll need AI to really tease out what's off for a given situation.

Here's just a small (known) sampling of some interactions between hormones and endocannabinoids:

https://www.frontiersin.org/files/Articles/410103/fnbeh-12-00249-HTML/image_m/fnbeh-12-00249-t001.jpg

Picture the internal workings of a swiss watch with all those dials representing a hormone pathway at very sizes and cycles.

Now picture three more watches also interwoven for neurotransmitters, endocannabinoids, and immune agents. 

It's a Dali painting at this point!

As one simple example with progesterone:

Like androgens and estrogens, progesterone can also regulate endocannabinoid signaling. Progesterone up-regulated the FAAH expression in T cells by interacting with a transcription factor in the promoter region of the faah gene

https://academic.oup.com/endo/article/153/3/1016/2423624

Ummm....what?

We covered FAAH in our article on CBD and the woman who can't feel pain or anxiety here.

That's one of a million different examples.  Seriously complicated stuff.

Schizophrenia is a perfect example.

Scientists agree that it's a complicated, multifaceted disease with elements of brain area communication, genetics, neurotransmitters, inflammation, gut biome issues, and even hormones.

 

The fact that both CBD and pregnenolone showed very impressive effects to improve not only mood (pregnenolone) but also brain activity (see CBD and schizophrenia) is simply put...astounding.

The other antipsychotics are minimally helpful at best (with terrible side effects).

Pregnenolone's status as an endocannabinoid was found by its effect to counter the psychoactive effects of THC:

∆9-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1receptor, reduces several effects of THC. 

https://science.sciencemag.org/content/343/6166/94

Other hormones directly interact with endocannabinoids (such as anandamide and 2-AG) but pregnenolone can "talk" directly with the CB1 (endocannabinoid receptors in the brain and nervous system) receptor.

If pregnenolone increased all hormones equally, that would be an issue.

Boosting cortisol would affect sleep and irritability.

It is the "stress' hormone after all.  More on cortisol.

We need more research but perhaps, the endocannabinoid system "hat" that pregnenolone wears allows it to act in this balancing capacity.

We're excited to see what researchers find.

Schizophrenia is one aspect (albeit, a complicated one).  What are the other reported benefits of healthy pregnenolone levels?

Benefits of health pregnenolone levels

There are some pretty good websites that walk through the benefits of pregnenolone (here for example).

The wide array of benefits is expected since we're dealing with hormones and they touch on almost every aspect of our health.

We'll give a summary level review here as they largely group around:

• Improves Mood (depression and anxiety)
• Improves Sleep Quality
• Improves cognitive functioning (memory and focus)
• Counters Stress and Fatigue
• Protects Nerves and nervous system

 

Let's take some snapshots of the above areas.

Improves mood (depression and anxiety)

 

A study found that people with depression, especially in an episode, had lower levels of pregnenolone:

CSF pregnenolone is decreased in subjects with affective illness, particularly during episodes of active depression.

https://www.ncbi.nlm.nih.gov/pubmed/8043707

A large study then studied pregnenolone effects on people with severe depression and bipolar:

In the pregnenolone group, baseline-to-exit change in the HRSA correlated negatively with changes in allopregnanolone (r(22)=−0.43, p=0.036) and pregNANolone (r(22)=−0.48, p=0.019) levels. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200497/

The HRSA is a test for depression.  Basically, the scores were better (lower) as pregnenolone and allopregnanolone levels increased (which they did).

Maybe more importantly...

Pregnenolone was well tolerated. 

In fact, the side effects were similar to the placebo group:

Overall side effect burden as assessed by the PRD-III was not significantly different between the groups 

 

The score dropped from 17 (average) to 9 on the test (out of 22 with zero being no depressive signs).

The same is true for anxiety and mood in general.

Starting with animal studies:

In animal models, social isolation is associated with anxiety, depression, and decreased pregnenolone levels.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200497/

Pregnenolone's real impact is on GABA.  We've covered CBD and GABA in detail here since that's the primary target of benzos for anxiety (the direct lever for anxiety).

We saw in the study above how pregnenolone increases levels of progesterone and allopregnanolone (significantly) above.

What does that do for GABA? 

The neurosteroids allopregnanolone and THDOC are strong positive allosteric modulators of the GABAAreceptors [48], but at a different site than the site bound by the barbiturates and the benzodiazepines  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573983/

Interesting.  What's the net effect of this?

Due to the increased probability of opening of the chloride channel of the GABAA receptor, neuroactive steroids increase a massive influx of the ion and potentiate inhibitory GABAergic transmission [49].

 

So more GABA flow, the target for benzos (addiction and tolerance) and CBD.

Just how strong compared to benzos and barbiturates (see CBD versus benzos):

The endogenous 3α-hydroxy ring A-reduced steroids such as ALLO and 3α,5α-THDOC are among the most potent ligands of the GABAA receptor, with affinities equal to or greater than those of other known ligands such as benzodiazepines or barbiturates.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC161645/

ALLO is short for allopregnanolone which we showed increases significantly with pregnenolone supplementation.  Equal or greater than benzos...without the tolerance.

We've discussed the effect of neurogenesis (replacing neurons) for anxiety and depression in our CBD and neurogenesis article. 

See our article on CBD and brain repair.

What about pregnenolone?

Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus.

https://www.ncbi.nlm.nih.gov/pubmed/15585350

Pregnenolone sulfate is a primary byproduct of pregnenolone with its own benefits in the brain.

Check out the CBD and hippocampus neurogenesis to understand just how powerful this effect is as we age.

Finally, all aspects of mood are affected by pregnenolone and its derivative hormones.

We looked at two double-blind studies on pregnenolone for schizophrenia and severe bi-polar above.

You can find hormonal effects at the root of all mood disorders.

Just one example since we're talking about neurogenesis and anxiety or depression to show how intermeshed this all is. 

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/

Estradiol (a down-river derivative of pregnenolone directly drives serotonin which we've discussed as the root driver of neurogenesis for SSRI's (see CBD versus SSRI's for anxiety and depression here).

I know this all too clearly from my bout with perimenopause and they go on to say:

This is one of the reasons why mood disorders are common in menopause – when estradiol goes away, so can serotonin.

 

We'll see more of this in the effects of allopregnanolone on postpartum depression below.

We hope to look at the effects in more detail across a range of specific mood issues (if we can ever finish this article!!).

Improves Sleep quality

This is dose-dependent and my experience is that it's best to take pregnenolone in the morning.

It can be excitatory depending on the state of your system.

That being said, my sleep is much deeper.

Research backs this.

Of course, it starts with animal studies:

Furthermore, neurosteroids such as pregnanolone, allopregnanolone, and pregnenolone are involved in the generation of slow-wave sleep, the effect has been demonstrated in experimental animal studies.

https://www.ncbi.nlm.nih.gov/pubmed/23092405

Pregnenolone Sulfate is a key player in regulating sleep quality:

Low concentration of PREG-S (5 ng) increased the amount of paradoxical sleep without any modification of slow-wave sleep and wakefulness. High levels of PREG-S (10 and 20 ng) increased paradoxical sleep and slow-wave sleep together with an increase of delta power and a decrease of theta power during wakefulness.  

https://www.ncbi.nlm.nih.gov/pubmed/15139033

Remember that our pregnenolone (from which preg-s comes from) drops by 70% as we get older.

No wonder older people have so many issues with sleep and perimenopause/menopause counts insomnia as a key attribute.

Unfortunately, our body and brain "housekeeping" occurs during this deep sleep.

In a human study, pregnenolone and preg-s were shown to increase deep sleep and it appeared to be via the GABA receptors we discussed above with anxiety:

P increased the amount of time spent in slow-wave sleep and depressed EEG sigma power. 

https://www.ncbi.nlm.nih.gov/pubmed/8395958

A recent study showed that one night of bad sleep was indistinguishable from a state of high anxiety in brain scans!

Learn more about CBD and sleep here.

Improves cognitive functioning (memory and focus)

There's a lot here so we're only going to touch on some highlights.

When you're mind is functioning at full speed, a lot has to go right including a wide range of hormone-neurotransmitter interactions.

Remember what it felt like to be 18 and everything was firing on full cylinders?

We'll offer one example (of many) from studies:

Researchers found that pregnenolone's positive effect on memory and learning was by activating NDMA pathways:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026085/

This subject is so involved and multifaceted that we'll have to save it for another article.

Counters Stress and Fatigue

This goes back to the original discovery of pregnenolone in the '50s.

They tested it for students and factory workers originally:

Productivity increased most notably in the workers whose situations were considered the most stressful; for example, the workers who got paid per piece and whose living depended on their productivity

https://www.grc.com/health/research/Pregnenolone/Pregnenolone_Review.pdf

Not only did pregnenolone improve productivity for both groups, but the workers reported enhanced mood. 

There's newer research which points to how this works.

For example, women with chronic fatigue syndrome have elevated amounts of iso-pregnenolone which counters allopregnanolone in the nervous system. 

https://www.ncbi.nlm.nih.gov/pubmed/14604604

Interestingly, the study resolved that the underlying cause of chronic fatigue may not be due to depression!

These results suggest that increases in ring A-reduced progesterone metabolites, particularly allopregnanolone, are associated with CFS, and that the pathophysiology of CFS is unlikely to be due to depression.

 

CFS is chronic fatigue syndrome. 

See our article on How CBD affects CRF corticotrophin-releasing factors and anxiety. 

Again, we need a full article on pregnanolones effect on energy and fatigue.

I personally take it in the morning as I do get energy from it.

Some people may feel a bit too much energy (jittery, etc) which is dose-dependent.

Just go down in dose to find your sweet spot.

Finally...my favorite area!

Protects and Rebuilds Nerves and nervous system

One of my final two symptoms that CBD and supplements did not wipe out was in my feet!

Extremely painful heel pain in both feet for no discernible reason.

Yes, I saw 4 foot doctors, an acupuncturist, and even a chiropractor.

It was hard to walk through most of the day.

The usual suspects of plantar fasciitis etc were ruled out.

It was nerve pain or just pain in general.

Most of that went away elsewhere in the body but my feet continued to hurt.

Pregnenolone basically reduced the pain within days.

What could account for this?

Let's look at pregnenolone's powerful effect on nerves.

Remember how progesterone was boosted from pregnenolone supplementation (the schizophrenia study)?

it was demonstrated that progesterone synthesis by Schwann cells, the myelinating cells of the peripheral nervous system (PNS), plays an important role in the myelination of peripheral nerves

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3274763/

This is huge!

Myline is the protective sheath around nerves that are critical to protecting, growing, and repairing nerves throughout the body!

Including in my feet (a very prominent nerve branch runs right under the fatty pad that makes up the bottom of your heel).  

A key symptom of perimenopause is….joint pain!

More research shows that pregnanolone is key to building the skeleton of neurons and nerves called microtubules.

https://www.ncbi.nlm.nih.gov/pubmed/23955365

The net effect of this:

Pregnenolone (P5) is a neurosteroid that improves memory and neurological recovery. 

 

Therefore it's not surprising that: 

Clinical studies demonstrated low circulating levels of PREG in the elderly, including those with dementia 

https://onlinelibrary.wiley.com/doi/full/10.1111/pcn.12150

There are studies on the pregnenolone metabolite for recovery from traumatic brain injury as well:

Combination Treatment with Progesterone and Vitamin D Hormone May Be More Effective than Monotherapy for Nervous System Injury and Disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025702/

We have a whole review on Vitamin D since it's also a steroid we get from the sun. 

Again, we need another article for this topic.

 

Let's jump to some specific questions people usually have about pregnenolone.

Are there downsides?

The pregnenolone and DHEA warning plus side effects

There's a pretty good run through the California warning for pregnenolone and DHEA here:

https://www.lifeextension.com/Magazine/2011/7/State-of-California-Decrees-Strong-Warning-Labels-on-DHEA-and-Pregnenolone/Page-01

The warning generally revolves around hormone-related issues.

There is old information on the effects of synthetic estrogens (which is why we only want bioidentical) and various issues.  Did a huge review estradiol safety.

With pregnenolone, we're boosting the raw material of hormones themselves.

It's curious to us that somehow, glyphosate and the myriad of endocrine disruptors that we're swimming in (plastics anyone) somehow don't get the same warning.

Anyway...read the review above for more detail.  They do a pretty good job of going through it.

It feels similar to when my doctor said I was going to have a stroke from taking bioidentical progesterone (when mine plummeted).

Now with the Dutch test, I can see exactly what my levels are and how my body methylates and metabolizes my hormones!

Pregnenolone will need a separate test but if you're over 40, it's a good guess that your numbers have dropped.

What about side effects for pregnenolone?

In the major studies we looked at above, they showed it was well-tolerated at 500 mg per day (I'm currently on 10-50 mg).

Some people do respond that they feel jittery or too ramped up.

I had that at 50 mg so I brought it down to 10 and slowly increased to find the spot below that threshold.

It can be excitatory so balance is key.

We'll discuss sources below down to 10 mg capsules for this approach.

We know from the studies that it boosts progesterone pretty strongly and allopregnanolone very significantly.

Allopregnanolone and pregnenolone for postpartum depression

We have a whole separate article on allo and depression.

The FDA just approved a drug, Zulresso (brexanolone) for postpartum depression.

It costs between $25K and $35K with hospital overnight required.

What is Zulresso?

ZULRESSO contains brexanolone, a neuroactive steroid gamma-aminobutyric acid (GABA) A receptor positive modulator, that is chemically identical to endogenous allopregnanolone. 

https://assets.sagerx.com/zulresso/prescribing-information.pdf

Wait what??

Did you catch the last part?  "Chemically identical to endogenous allopregnanolone".

Yes, it's allopregnanolone which is boosted significantly from pregnenolone supplementation.

You can't patent pregnenolone however since it's a naturally occurring hormone.

The issue is that any time we've seen a synthetic hormone or endocannabinoid (rimonabant as an example), there's a slew of side effects that come with it.

"Chemically identical" is not identical.

Again, we want to investigate this whole topic separately but when we looked up the core mechanism behind this $25K drug, we were so angry.

More importantly, the researchers knew that allopregnanolone could help poor women with postpartum depression (1 in 9 pregnant women by the way) and they waited for all the processing (years) to make money off of it.

 

Shame on them.

What CBD and Pregnenolone have in common

Our entire site is filled with research on CBD.

Why the sudden pivot to pregnenolone?

First, when we find something in the research that is helping people, we want to research it.

Secondly, I personally wanted the benefits of pregnenolone for perimenopause issues.

Finally, CBD and pregnenolone have a lot in common:

They both are endocannabinoids in that they affect CB receptors.

 

In similar ways!

They are both "allosteric modulators of the CB1 receptor".

That's a mouthful.

Basically, they both do the exact same thing for CB1 receptors in the brain and nervous system.

CBD also can affect CB2 receptors throughout the body.

This is interesting for many reasons.

First, they appear to have similar effects on many-core systems such as GABA (see CBD and GABA) which is critical for anxiety (too little), depression (too much), ADHD, and almost every mood disorder.

 

This may also speak to why pregnenolone safety profile is so strong even at the 500 mg in the studies above.

We haven't found a study on overdose for either CBD or pregnenolone.

The endocannabinoid system is about balancing other key systems.

We await further research showing the cross-section between pregnenolone and CBD.

Best time of day to take pregnenolone

Even though it deepens sleep, the initial response for pregnenolone can be energy and focus.

For this reason, I take it in the morning and some athletes take it before working out.

In the morning with food would be ideal.

Make sure to take it at least 2 hours away from any medications (after clearing with a doctor who hopefully even knows what it is) since it uses the same, busy p450 pathway for processing.

Can you test for pregnenolone levels

Yes but it's almost never done.

I have seen 5+ doctors of all different preferences and have yet to get a pregnenolone test.

This in spite of being almost 50 years old and knowing that core levels drop significantly as we get older.

The gold medal Dutch test for hormones doesn't even cover it.

I did find a pregnenolone test directly here. 

I actually got a test right through Quest lab and it came back at 123 (after supplementing for 30 days).   

 

I want to get it up to 180 based on the recommendations we've received.

Once I saw my numbers were low, what's the best pregnenolone?

Best pregnenolone

The first consideration is how mg of pregnenolone to start with.

I bought my first one at WholeFoods (MRM brand) at 50 mg.

It almost immediately helped my sleep and foot pain but I also felt pretty amped up for a few hours after taking it.

I then switched to Country Life at 10mg here since I wanted to start with lower levels.

My goal was to increase in increments of 10 mg until I reached that point of too much energy.

Everyone is different obviously!

The "micronized" version from MRM did appear to have a stronger effect. 

Do I need a prescription for pregnenolone

No.  Pregnenolone is treated as a food supplement.

You can buy it online at iherb here.

Again, technically, it's not a hormone but a precursor to hormones, steroids, and even an endocannabinoid.

Goodness...what have we stumbled on here?

Related Research:

CBD and Perimenopause symptoms and questions

Vitamin D Review

Estrogen and mental health

Progesterone guide

Steroidal hormone and longevity

Steroid replacement to edit health code

 

 

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.