Lowering Allopregnanolone in PSSD

Therapeutic Efforts Pharmaceutical
#1

Hey guys, I have PSSD. Please note, these are just my personal views.

My Theory is that in PSSD there is a increased Allopregnanolone level (in contrast to PFS) leading to constant high GABA signalling (Allopregnanolone is a potent PAM of GABA), this high GABA signalling inhibits glutamate and LTP function aswell as neurogenesis. Its like im on a benzo 24/7.

The brain shifted to a inhibitory dominant type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC23979/ (46 fold increase from DHP to allopregnanolone!)

“The efficiency of the enzyme, the ratio of V max to K m, then was calculated. The enzymatic efficiency of rat 3α-HSD, in the conversion from DHP to allopregnanolone, was 3.7 and was 0.003 in the conversion of allopregnanolone to DHP. The enzyme efficiency of the reductive reaction increased ≈46-fold in the presence of fluoxetine. Fluoxetine did not alter the oxidative reaction. Thus, fluoxetine dramatically enhances the efficiency of the enzyme, but only in the conversion of DHP to allopregnanolone.”

There exists a class of so called GAMSAs https://pubmed.ncbi.nlm.nih.gov/26523675/

These would lower GABA signalling by inhibiting the action of the neurosteroids Allopregnanolone and THDOC. https://en.wikipedia.org/wiki/Golexanolone

Unfortunately these are RCs and very hard to get.

I wondered if there are other ways to target this high GABA signalling that is blocking. Normal GABA antagonists like flumazenil won’t work in that case as GABA’s activation is coming from the high Allopregnanolone levels.

Maybe one could try to inhibit something upstream,with something like Mifepristone?

Another way I thought of trying was to inhibit 5AR with Zinc or something but that is likely too weak.

The idea was to lower the GABA signalling and simultaneously increase glutamate/LTP/neurogenesis again by using neurotrophic agents like P21 and NSI-189, so once the brain shifts to a more excitatory type the GAMSA will not be needed anymore. Hopefully this would also correct all downstream hormonal changes and make the brain and body respond to hormones again.

Would be grateful for suggestions.

#2

Is there more evidence to support long-term induction of 5ar and/or 3a-HSD activity after withdrawal of an SSRI?

The main reason I’m pointing this out is a rat study observed a drastic decrease in baseline enzyme activity (and allo levels) after chronic administration of fluoxetine, followed by abrupt withdrawal:

. https://pubmed.ncbi.nlm.nih.gov/11685383/

Results: A single dose of fluoxetine (20 mg/kg, i.p.) induced in 20 min significant increases in the cerebral cortical and plasma concentrations of 3alpha,5alpha-TH PROG (+96% and +13%, respectively), 3alpha,5alpha-TH DOC (+129 and +31%, respectively), progesterone (+111 and +58%, respectively), and pregnenolone (+151 and +59%, respectively). In addition, the plasma concentration of corticosterone was also significantly increased (+24%) after acute administration of fluoxetine. In contrast, long-term administration of fluoxetine reduced the basal concentrations of these various steroids (ranging from -22 to -43%), measured 48 h after the last drug injection, in both brain and plasma. A challenge injection of fluoxetine (20 mg/kg, i.p.), however, was still able to increase the concentrations of steroids in both the brain and plasma of rats chronically treated with this drug. Acute foot-shock stress increased the cortical and plasma concentrations of steroids in rats chronically treated with fluoxetine to extents similar to those apparent in control rats.

The apparent symptom overlap between PSSD patients and PFS patients also seems contrary to suspecting increased neurosteroidogenic enzymes in PSSD?

1 Like
#3

Interesting study.

If SSRIs raise Allopregnanolone but then once you stop it then it lowers Allopregnanolone , then the remaining excess GABA might be from excess GABA beeing present for so long - leading to excess synaptic pruning & the impairment of LTP-dependent formation of useful neural connections
 so when the SSRI is stopped, the brain has already lost so much of its excitatory ability. So the brain is still in a net inhibitory state as result.

5a-DHP converts to allopreg 40 fold more on SSRIs.

If that down regulates 5a-DHP production, then getting off SSRIs might cause 5a-DHP to upregulate. Unlike allopreg, 5a-DHP has genetic ability to increase GABA receptors


https://www.pnas.org/content/98/5/2849

This means turning off 5a-DHP may reverse the genetic effects that are causing constant creation of excess GABA receptors far after SSRI cessation. Nevertheless, a GAMSA will confirm if this is the source of the excess GABA by reversing the acute effects of excess GABA - then neurogenesis of glutamate receptors & useful LTP-induced neural connections can form while looking for a way to downregulate 5a-DHP. Although, restoring excitation temporarily while inducing neurogenesis may help hormones upstream of 5a-DHP improve the regulation of 5a-DHP
 but specifically targeting the turning off 5a-DHP (without causing too much rebound/upregulation) may be required in later stages to not need GAMSAs anymore

#4


So, basically take a drug with 5-ari activity to satisfy a huge supposition about PSSD?
I think @borax already tried this experiment unintentionally with undesired results.

#5

Im not sure about this step yet.

@borax is a fin case mostly though?

#6
#7

I first took antidepressants at the age of 14/15 for a short period. I wasn’t depressed, just dissatisfied with some things in my life, but the doctor I met prescribed me SSRIs after speaking to me for less than 5 minutes. This is not an exaggeration, he just ran through a check list of symptoms (“Do you sleep more than normal?”, “Do you feel unhappy?”), didn’t ask me a single thing about why I was feeling the way I was, and gave me a script for Prozac.

I used that for a couple of weeks, and at some point, he switched me to Cipralex, which I also took for a short time.

After this, I had slightly numb genitals (never came from penetrative sex), and some minor issues with motivation and libido. It wasn’t disabling in any real way though, and the thought that something was wrong with me never even occurred.

Then I made the mistake of taking Finasteride. Oh boy, the first time I took it for four days and dropped it, it made me go back to normal essentially. My libido was higher, my sensitivity was high, my performance in the gym was great, my motivation was through the roof, etc. I felt like I was about to conquer the world. I took Finasteride again, and then I got PFS.

A piece of advice: there is no point theorizing about this stuff. We have a theory that has gotten some form of confirmation (the study that showed AR overexpression in the penile tissue of PFS patients, and found that AR overexpression was directly proportional to the degree of symptom severity) of the prevailing theory. I think this is the path to go down.

If PSSD and PFS are the same disease (and my experience with both classes of drugs and the way they affected me leads me to strongly believe that they are the same), then it’s essential that we get together as a community, back this hypothesis, and try to get research done related to this. Theorizing is just a distraction that takes precious time and energy away from these goals.

4 Likes
#8

Fascinating.

#9

@borax thanks for checking in
@orthogs whats fascinating?

#10

The Benzodiazepines have been a lifesaver for me. I wouldn’t be able to function at all without them. I have severe anxiety and insomnia and greasy skin and countless other things when I’m off of them.

1 Like
#11

I see PFS people often have increased anxiety. Where in PSSD they have no anxiety response anymore (like in me). Its not the same for everyone though of course

#12

Borax’s story.

#13

Agree.

#14

After I quit using finasteride, I first started having severe insomnia and sky high anxiety. My skin was very greasy as well. Taking Klonopin helped with joint and muscle pain as well. I truly believe that finasteride screwed up my neurotransmitters. After I quit finasteride, I tried the drug Wellbutrin, and for a couple of days I felt completely normal. Then I went back to feeling lousy.