CBD and Pregnenolone for the Pathways of Postpartum Depression

CBD and pregnenolone for post partum depression

There are exciting new advances in regards to postpartum depression.


We'll walk through the mechanics of the blockbuster new drug but more importantly, we'll look at how it works and a simple option to affect the same pathway.


Along the way, we have to touch on the power of estrogen when it's in flux.


Finally, let's look at CBD and its effect on serotonin.


Lots to cover the net takeaway is this: 

The treatment for postpartum depression has radically changed in the last few years and we can dissect exactly what's going on there.


Very exciting.


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Here are the topics we'll cover: 

  • What causes postpartum depression
  • The power of estrogen for mood and depression
  • The new blockbuster postpartum depression drug, Zulresso and how it works
  • Pregnenolone and Allopregnanolone for postpartum depression
  • BDNF, the star of the postpartum depression story
  • CBD for the pathways of postpartum depression
  • How much CBD and pregnenolone for postpartum depression
  • What's the best CBD and pregnenolone for postpartum depression


Let's get started!

What causes postpartum depression 

This takes us deep into the powerful world of hormones.


Essentially, a flux or sudden change in hormones.


After delivery, our two key hormones, progesterone, and estrogen, can drop significantly.


Mother nature is all about conservation and these key hormones for birth and delivery also have impressive roles elsewhere in the body and brain


In fact, reproduction is just the main stage with many other stages of equal importance.


Let's take just two examples:


  • Progesterone directly boosts GABA, our calming neurotransmitters (see CBD and GABA)
  • Estrogen directly boosts serotonin, the master regulator of all human behavior!


That second one is really important for postpartum depression.


If serotonin goes too low, you have a range of issues including: 

  • anxiety.
  • depressed mood.
  • aggression.
  • impulsive behavior.
  • insomnia.
  • irritability.
  • low self-esteem.
  • poor appetite. 



Okay...let's look at postpartum effects.


  • Depressed mood or severe mood swings
  • Excessive crying
  • Difficulty bonding with your baby
  • Withdrawing from family and friends
  • Loss of appetite or eating much more than usual
  • Inability to sleep (insomnia) or sleeping too much
  • Overwhelming fatigue or loss of energy
  • Reduced interest and pleasure in activities you used to enjoy
  • Intense irritability and anger
  • Fear that you're not a good mother
  • Hopelessness
  • Feelings of worthlessness, shame, guilt, or inadequacy
  • Diminished ability to think clearly, concentrate or make decisions
  • Restlessness
  • Severe anxiety and panic attacks
  • Thoughts of harming yourself or your baby
  • Recurrent thoughts of death or suicide 



Okay...so complete overlap.


Like we said...serotonin controls all human behavior...right down to self-esteem.


Too much serotonin is also bad and leads to a host of issues, some very dangerous.


To add some emphasis, SSRIs, the leading medication for depression, directly boost the availability of serotonin.


We did a deep dive on exactly how SSRIs work or CBD versus SSRIs.


The issue is that they build tolerance (actually push your natural serotonin production down).


Just know that serotonin balance and function is the key driver there.


Progesterone is no slouch, however.


This is the primary hormone of pregnancy and it can drop rapidly after delivery.


Aside from GABA, our calming and stress buttress, progesterone has a secret metabolite up its sleeve which we'll look at later (the basis for new postpartum depression med).


A possible explanation is that progesterone and its cerebral metabolite known as allopregnanolone seem to decrease irritability.  



Interestingly, progesterone doesn't really kick back up till the first period after delivery.


If you're nursing, this can be quite some time!


Needless to say, having a newborn is very stressful and now our main calming agent (target for benzos - see CBD versus benzos) drops through the floor.


As we detail in our CBD and depression review, stress and other insults can overwhelm the prefrontal cortex, the area behind your forehead which is critical for keep fear centers at bay and just feeling "connected".


We'll look at the key push back on this attack called BDNF below.


It may be your new best friend and both progesterone and estrogen directly drive it!


So...we're losing the calming agent (progesterone) in our brain and nervous system and we're losing the mood stabilizer (estrogen) in our brain.




And those hormones are just for reproduction (sarc).


It's not just postpartum where we see this effect.


In fact, we found CBD due to a brutal perimenopause (story is here) where estrogen goes into a roller coaster for roughly half the women approaching menopause.


Check out CBD and perimenopause depression to see the same process.


Monthly cycles and puberty can be equally chaotic depending on how severe the changes are in key hormones.


It appears to be the rate of change that really matters.


Animal studies are pointing to this effect in controlled settings: 

The rapid decline of hormones induced an increased startle response lasting for two days and increased anxiety-like behavior in the open field. This was not found in the gradual-decline and control groups.



Brains can compensate for sudden drops but it can take up to 30 days for genes to be turned on and off to adjust.  We see that quite clearly with addiction and recovery studies (see CBD and addiction).


There are other secondary hormones at play but the big ones are progesterone and estrogen which tend to have their hands in many pies downstream.


Speaking of downstream, let's look at a curious metabolite of progesterone called allopregnanolone.


It may be your new best friend!

The new blockbuster postpartum depression drug, Zulresso and how it works 

It's only 2019 that we got this new drug.


It has been described as a total game-change for postpartum depression which before, was really not well treated.


It costs about $25,000 and requires an overnight stay at a hospital.


Here's the fascinating piece.


Zulresso is essentially a synthetic version of an existing (and very inexpensive) hormone called allopregnanolone.


That makes it hard to patent so a synthetic offers billions of dollars in revenue (we're jaded but unfortunately, correct).


The results are pretty fast (60 hours) and immediate: 

In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19·5 points (SE 1·2) in the BRX60 group and 17·7 points (1·2) in the BRX90 group compared with 14·0 points (1·1) in the placebo group 



The HAM-D is a test for depression with a total of 17 questions and 5 answers for each.


Essentially a scoring from 0 (no depression) to 52 (max on all questions).


The above test showed a drop of 19 points which is very impressive.  Interestingly, placebo scored a 14 point drop.


19 points out of 52 are very significant.  The 60-hour mark is also very fast!


The results continued at the 30-day mark.


These tests were double-blind, placebo driven which is important.


The side effects were mild but still present compared to the bioidentical pregnenolone or allopregnanolone.


Let's now dive deeper into this root pathway.

Pregnenolone and Allopregnanolone for postpartum depression 

As we mentioned, progesterone is the main hormone for birth.


It can drop significantly after delivery and stay suppressed until your first cycle.


What's interesting is hormones operate on a cascade of different metabolites or breakdowns.


One particular one that is made from progesterone is allopregnanolone.


It was mentioned above as preventing irritability but it goes much deeper than that.


As we saw above, the synthetic version of this hormone has a powerful and almost immediate effect on postpartum depression.


What gives?


First, allopregnanolone directly drives and controls GABA function, our calming agents in the brain from above: 

In 1986, Paul's laboratory observed allopregnanolone is a potent positive allosteric modulator of GABA's action at synaptic and extrasynaptic GABAA receptors  



Put a checkmark next to stress, insomnia, and anxiety with tangential impacts on depression.


Interestingly, allopregnanolone is an "on-call" hormone that's quickly ramped up when needed...usually due to stress.


With chronic stress, however, allopregnanolone can "burn out" and become less responsive.


We see this same effect in many pathways from pain to insulin.


Here's the kicker for birth: 

The increase in plasma progesterone throughout pregnancy triggers upregulation of allopregnanolone levels, which reaches the highest blood concentrations during the third trimester  



This makes sense...the body is getting ready for the stress of delivery...max levels!


And then...nothing.  Or at least in some women and the effects of this are pronounced.


The net effect?


Reduced levels of allopregnanolone are found to be associated with major depression, anxiety disorders, premenstrual dysphoric disorder, and Alzheimer’s disease. 



Interestingly, you can get a supplement called pregnenolone here for about $10.


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It's the mother of all steroidal hormones including progesterone but here's the important piece: 

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 



Goodness...a 5 fold increase in allopregnanolone, the basis for the synthetic postpartum drug at $25K.


This is revolutionary and also very very sad for our health delivery system.


You should be both relieved and a little bit angry upon learning about this.  We'll take anger over depression any day!


We did a monster review on pregnenolone since this effect is only the beginning.


It just so happens to be a critical piece with postpartum depression.


That's all well and good, but we're going deeper down the rabbit's hole to find the underlying basis for benefit.



BDNF, the star of the postpartum depression story 

Every time we dive deep into a mental health issue (see CBD and mental health), we end up at the same place.




Short for the brain-derived neurotrophic factor.


It's essentially the fertilizer for our brain and it is the real star of the show for depression.


Here's the basic mechanics (see CBD and depression for more).


BDNF is the primary defense against a host of brain-withering assailants: 

  • Chronic stress
  • Trauma
  • Hyperactive immune response
  • Excessive GABA
  • Drugs and alcohol
  • Medications
  • Gut and brain barrier weakness


Check out CBD and BDNF or CBD and brain repair to learn more.


What's the connection here?


The protagonist in this mechanism is likely the brain-derived neurotrophic factor (BFNF), which is decreased in animal models of depression and maybe restored by the normalization of allopregnanolone levels.  



People...BDNF is THE key here.


In fact, when BDNF is blocked, SSRIs lose their anti-depressive effects.


When BDNF is blocked, the endocannabinoid system (where CBD works) loses its effects.


We are pretty sure that if BDNF is blocked, allopregnanolone will also suffer the same fate.


It really is becoming the most important player in mental health across almost every issue.


What boosts BDNF besides allopreg: 

  • Exercise
  • Mindful meditation
  • Psilocybin
  • Serotonin (thus the estrogen effect)
  • CBD


Okay...that's a great segue.

CBD for the pathways of postpartum depression 

A quick introduction if you're new to CBD.


It's a substance naturally occurring in the cannabis plant but it's completely different from THC (which drives the "high" feeling).


In fact, CBD and pregnenolone have both been shown to offset the negatives of THC in the brains!


They're commonly used for "greening out" or when someone takes too much CBD for this reason.


See CBD versus THC for more.


Here's the fascinating connection: 


Pregnenolone can directly affect the CB1 (endocannabinoid) receptors:

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



Don't worry...we'll break this down because it's very intriguing.


Essentially, it works like a feedback mechanism for the endocannabinoid system.


Guess what else is a prominent negative allosteric modulator for GABA and serotonin?




Here's the full listing of its primary pathways but GABA and serotonin are all over our discussion for postpartum depression.


Remember that progesterone boosts GABA and estrogen boosts serotonin.


Based on the above, does CBD have an effect there?


The maximal level of enhancement seen with either CBD or 2-AG were on α2-containing GABAA receptor subtypes, with approximately a 4-fold enhancement of the GABA EC5 evoked current, more than twice the potentiation seen with other α-subunit receptor combinations. 



A 4x's increase in GABA function.


Interestingly, it doesn't keep pushing in one direction the way benzos do (see CBD versus benzos).


That's why we don't see sedation and other effects from CBD and speaks to the "feedback" mechanism.


Very important as we don't want to develop tolerance.


We have a full review of CBD and GABA here.


Key to insomnia, anxiety, and more.


What about Serotonin, our master mood regulator?


This is even more interesting!


CBD supports serotonin but only when it's depleted!


A study looked at the effect of chronic pain (which eats up serotonin) and found the following: 

Overall, repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions. 



Let's break it down because it's really important.


Essentially, CBD  "rescued" serotonin (5HT) transmission.


Resue is key there because we don't want to keep jacking up serotonin in one direction slike SSRIs or we can get serotonin syndrome (too much serotonin - just as bad as not enough).


Research does not show serotonin syndrome with even high doses up to 1.5 grams (1500 mg).


We have lots of research like this at our  CBD and serotonin review. 


Now...remember how serotonin drives BDNF and it's the key star behind SSRIs and any antidepressant effect.


We also learned that allopregnanolone, the blockbuster drug for postpartum essentially boosts BDNF as well.


What about CBD?


Get ready for this: 

Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex



Let's break that down because it's too important: 

  • CBD boosts BDNF
  • As a result, it has an anti-depressant effect
  • Which leads to creating of new connections in the...prefrontal cortex!


Yes, the area right behind your forehead which is key to depression.


We have a whole review on CBD and BDNF or CBD and neurogenesis here.


Now you see why we're so excited?


CBD and pregnenolone could be powerful players with very strong safety profiles.


In fact, every time we've looked at synthetics, they perform worse in terms of side effect profiles.


The synthetic hormones (progesterone and estrogen) have completely different safety effects (worse) than bio-identical ones.


This would be all over the news if it wasn't so profitable.


Let's look at practical questions.


How much CBD and pregnenolone for post pardum depression


For CBD, we have interesting research that shows the neurogenesis effect (repair and rebuild) effect driven by BDNF peaks at 300 mg daily.


This can be broken up and of course, that's the peak levels.


Some people may find lower amounts work fine.


There can be an immediate effect (GABA) but the longer-term serotonin and BDNF effects take about 14 days to kick in.


Since the allopreg worked within 60 hours, this really points to GABA as being the immediate relief on the nervous system (and prefrontal cortex).


Since CBD works on both GABA and serotonin, there's an immediate and longer-term effect.


In terms of pregnenolone, the above (for schizophrenia - see CBD and psychosis) was 500 mg daily for 8 weeks.


That study showed a 5 times increase in allopregnanolone.


What type of CBD and preg?

What's the best CBD and pregnenolone for postpartum depression 

For CBD, there are basic requirements for everyone but especially new mothers: 

  • Organically grown in the US at FDA registered farms
  • CO2 processed
  • 3rd party tested
  • NO THC - very important especially if nursing
  • No pesticides
  • No heavy metals
  • No solvents
  • No mold
  • No bacteria


We focus on CBD isolate to make it very clean...just two ingredients: 

  • CBD isolate (CBD by itself)
  • MCT oil from organic coconuts


Histamine response (allergies) can explode following birth since progesterone is a powerful immune controller and it just left the building.


For this reason, we want to avoid full-spectrum CBD with all the plant material involved.


THC is a total no-go as it pushing pathways in one direction and affect neurodevelopment and hormones.


We did a big review on CBD and hormones to show it doesn't affect this key manager.


The 6000 mg bottle is priced at about 2-3 cents per mg before discounts up to 50%.


One dropper is about 200 mg which is close to the 300 mg peak for neurogenesis.


For pregnenolone, we personally use LifeExtension and they have 50 or 100 mg levels.


Preg is the mother of all steroidal hormones so you can start low and work your way up.


The 500 mg level referenced above may be higher than needed (it was for schizophrenia after-all).


Preg can give energy so we take it in the morning.


All and all, this is exciting new information for women with postpartum depression and we wanted to shed light on the underlying mechanics to see how to affect those directly.


Be well. Take care of each other.  Take care of yourself.


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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.

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