PFS caused by Neurosteroid pathway interruption?

General Discussion
#10

Comes as 20mg pills, I chop into 1/8ths with a pill cutter, which makes it 2.5mg, then because of the long half life you can just take it every second day to have it average out to be 1.25mg. The half life is something like 4-6 days, so you don’t need to be taking it daily.

I tried Desvenlafaxine (SNRI) at 50-100mg before Fluoxetine, and did not get the same benefits, so it’s definitely not placebo. Please be careful, so many people have been damaged from SSRIs!! I only want to share my experience.

#11

Thanks mate - all the best with your recovery and will share any updates / progress I make

#12

Hi @scott7777 ,

Glad to hear you at least saw some improvements since that damn first pill.

I took a single pill too and I’m still struggling with sexual sides, I was wondering if you had any and if it improved?

I am devastated and looking to hear experiences of other one pill users. It seems like we are the minority of the minority.

Cheers

#13

Hey man,

I know it sucks, I am 27 now but took the pill at the age of 21. Such a small minority of guys have to deal with hair loss at the age of 21 and then an even smaller minority are unlucky enough to have persistent PFS years later, let alone any side effects to begin with. We are the unlucky 1% of the 1%…! Anyway - we must keep up the fight!

I didn’t ever experience any sexual sides. Just very very severe mental / cognition issues which have gradually improved over time. I therefore can’t offer any specific advice on your condition.

That being said - I am a believer that this is reversible, either as your body gradually readjusts over time or by pharmacological interventions. This is so hard to treat because PFS is caused by interference with really complex endocrine and nuerosteroid pathways - way beyond issues with just Test / DHT levels (which is where most people look). Therefore, you need to know where to look in order to find what is off balance and infer any potential treatment options.

For myself and my mental sides, as per the above initial post, I am pretty sure that the drug interfered with my Allopregnenolone levels. When talking about sexual sides, I think there are a number of potential causes. Obviously there could be some sort of Test / DHT issue caused directly by Fin (although Test & DHT levels in sufferers are usually not in an abnormal range). Alternatively, through a few different pathways oestrogen levels could have been raised or potentially there could have been up/downregulation in androgen receptors.

Have you had any bloodwork done? I personally do not know enough to explicitly advise, however there are some online experts who understand this stuff down to a really granular level, one of whom is linked above (Leo Longevity), another is Derek from MorePlatesMoreDates.com.

It may be helpful for you to pay for a private consultation with one of them, they have a track record of helping correct chemical imbalances of PFS sufferers and can help you identify what bloodwork you should have done and thereafter what some potential treatment options could be.

These guys are not Physicians, therefore any advice they give etc should be discussed with a Doctor. However, I think most doctors are clueless in terms of knowing where to start - I think these guys could help you start looking in the right places.

Good luck man, keep fighting…

#14

Yes man. The worst part of my story is I didn’t need it. It’s crazy.

I will look into those guys thank you very much, it is greatly appreciated. I had bloodwork done 4 days after the pill (which was fine) and I am going back this week to compare.

I really hope this is reversible. I considered suicide at least 50 times through this whole mess. And I was the happiest camper ever before.

How are you doing 6 years later?

Thanks again man,

#16

Allopregnanolone is a positive allosteric modulator of the GABA receptors. Benzodiazepines are a positive allosteric modulator of the GABA receptors. Positive modulators of the GABA receptors are “enhancing” the GABA receptors reaction to GABA. Benzodiazepines of course are doing this to a “stronger” degree compared to naturally made Allopregnanolone.

There are positive and negative allosteric modulators of the GABA receptors

3a-diol is also a positive allosteric modulator of the GABA receptor

Pregnenolone sulfate is a neurosteriod that I believe has been overlooked. Pregnenolone sulfate is a negative modulator of the GABA receptor. I am assuming that the GABA receptors need a proper balance of positive and negative modulation.

I’m flagged low in saliva pregnenolone sulfate suggesting that my GABA receptors lack NEGATIVE allosteric modulation. I have flagged high amounts of 3a-diol in my urine suggesting that my body is excreting/getting rid of high amounts of the neurosteriod 3a-diol which as previously stated is a POSITIVE allosteric modulator of the GABA receptors. I have highish Allopregnanolone in my urine suggesting that again my body is excreting another major natural POSITIVE allosteric modulator of the GABA receptors.

So I’m pretty sure everyone can see where I’m
trying to go with this. It’s possible evidence of a GABA imbalance/mis-regulation of some kind. Maybe what’s going on with me is that without negative allosteric modulation it makes sense that my GABA receptors could become too sensitive and then my body gets rid of positive allosteric modulators to “try to compensate”.

We also know that I agonized my NMDA receptors with just a slight increase in glutamate recently and I experienced “a crash” that felt identical to my Saw P crash seven years ago. I say “just a slight increase in glutamate” because I had before and after urine neurotransmitters testing done and I only had slightly higher glutamate in my urine after taking L-Glutamine for 64 days in between both urine neurotransmitter tests.

So because GABA receptors are the main inhibitory neurotransmitter receptors and the glutamate receptors are the main excitatory neurotransmitter receptors it’s important that these two things need to be in proper balance with each other. So if the GABA receptors are “out of wack” due to improper balance of positive and negative allosteric modulation it makes sense that the glutamate receptors would now be “out of wack” now as well. This could explain my “PFS type crash” response to simply agonizing the Glutamate receptors “just a little”.

We also have the user thisisarealbummer who came to a similar conclusion based on his own experience. And we have the other user who is narrowing in on the glutamate receptors who’s name I can’t remember at this moment.

I want to know if others would show a similar pattern if they were to have their saliva Pregnenolone sulfate, urine Allopregnanolone and urine 3a-diol tested. Two different tests from a company called ZRT lab are required to have all three things tested. For weeks I have been in contact with a ZRT lab provider in an attempt to make these tests available for others. I really want to know if what I’m seeing with low saliva pregnenolone sulfate, high urine Allopregnanolone and high urine 3a-diol can be replicated in others. The testing is not cheep but if this functional health company comes through for us it will be as cheep as possible and not require a doctors order. I may know more this week.

#17

If my current line of thinking is correct in my case in theory all it may take is increasing pregnenolone sulfate because I’m low in it and its a negative allosteric modulator of the GABA receptors. So maybe without a proper balance of negative and positive allosteric modulation the GABA receptors may not be able to function properly and this may throw off a proper balance between GABA and GLUTAMATE the bodies main inhibitory and excitatory neurotransmitters. This is just a theory though. We have not replicated my low saliva pregnenolone sulfate or my high urine Allopregnanolone and 3a-diol in anyone else yet. I’m trying to get others to get tested .

Allopregnanolone and 3a-diol are positive allosteric modulators of the GABA receptors

Recently I had a urine neurotransmitter test done. It showed I was low in Glutamate. I took a bunch of amino acids and SAMe and increased the amount of glutamate that my body was producing confirmed by a follow up urine neurotransmitter test. I crashed. Like a complete PFS type crash. I was so wired that I stayed up for 9 days. This was what happened to me when I took saw P seven years ago. The only thing that allowed me to sleep was benzodiazepines which I agree we should not be taking. Scared to death of continuing to get worse I stopped taking everything. Eventually I built up enough courage to add glycine back in which substantially helped me. I currently need at least 3500 MG’s of glycine to sleep. Interestingly even with taking 5000 MG’s of glycine I still have lowish amounts of glycine in my urine suggesting that my body needs that glycine. Probably because it’s inhibitory and maybe because I have a GABA/GLUTAMATE receptor imbalance. So maybe my body is using all this supplemental glycine to bind to the glycine receptors to compensate for the GABA receptors, the bodies main inhibitory neurotransmitter that may not be working properly. Glycine also binds to the glutamate receptors as well

2 Likes
#18

Why did you take it if you didn’t need it out of interest? Looking to preserve the hair you have?

Good luck man - I am sure that one way or another you will begin to improve. But keep me updated in terms of consultations & bloodwork etc.

I am around 95% healed now and I have learned to deal with the other 5%. I definitely continue to improve year on year though. I am pretty sure in the future I will be able to forget about this mess. It’s been a slow journey to where I am now though and mostly suffering in silence due to the embarrassment of it all.

Take care mate

#19

Thanks a lot for your response - this is insightful and interesting.

I would also agree that it is unlikely a case of just lacking positive modulation of GABA receptors and that a general mis-regulation is likely a more accurate description for PFS sufferers.

Can I ask what your symptoms were at the time that you hypothesise you had a lack of negative GABA modulation? I assume that such symptoms would be the opposite of ‘feeling wired’ and the symptoms we know that you get form a lack of positive modulation?

I would certainly be interested in neurosteroid tests. I suffered in silence for a long time because I couldn’t find a doctor that understood my condition. I think it is important that we create a set of possible diagnostic tests - that being said I live in the UK which may be prohibitive on the assumption you are further afield.

1 Like
#20

Still one of the most promosing theories.
Dysrupted 5ar=>Neurosteroid downstream=>desensitized (?) GABA what can explain no respond to alcohol etc. like you are always “high”. What success you had exactly with low dose SSRI? I also think about to try it.

1 Like
#21

My response to alcohol after getting PFS is very limited compared to pre PFS. And believe me I know because prior to PFS I liked to drink haha

Now it’s like I go right to the hang over and feeling like crap and skip the good feeling . So I stopped drinking a long time ago

I agree that this is one more clue that further implicates the GABA receptors. My theory is that if the GABA receptors which are the bodies main inhibitory neurotransmitter did in fact become intolerant per thisisarealbummers theory then the glutamate receptors as well as possibly the dopamine, adrenaline and noradrenaline receptors may all become mis-regulated in an attempt to match the intolerant GABA receptors

2 Likes
#22

So I’m currently 36. I got PFS from Saw-P at age 26. At that time I got all the sexual sides only. Not that sexual sides only don’t suck because they do. At age 29 I took saw-P again and developed digestive and insomnia issues on top of sexual sides.

Then recently as in this past summer after taking my recovery attempts to the next level I had one of the most advanced saliva hormone tests done currently available in a normal clinical setting. This is how I discovered that I’m low in a not so well know neurosteriod called pregnenolone sulfate. I’ll edit this post and include a chart later so that you can see where and how in the hormonal pathway pregnenolone sulfate is being made. Most of the hormonal pathway charts you find on line will not include it.

Then i started googling the heck out of pregnenolone sulfate leading me to discover that it’s a neurosteriod that negatively modulates the GABA receptors. The exact opposite as Allopregnanolone, 3a-diol and benzodiazepines which act as positive allosteric modulators of the GABA receptors.

Now if I’m low in the bodies main negative allosteric modulators of the GABA receptors it’s my theory that this is a possibly mechanism/scenario in which the result is that the GABA receptors may stay in a constant state of insensitivity/down regulation in order to avoid “excessive positively modulation”. Because maybe it’s the case that the GABA receptors need a proper balance of negative and positive modulation in order to stay “balanced” because after all that’s the point of a “modulator”.

So if there is no negative allosteric modulator present because there is no or not enough pregnenolone sulfate then maybe the “next best thing”is that the GABA receptors become less sensitive to the effect of the neurotransmitter GABA. And if this happens maybe the bodies main excitatory neurotransmitter glutamate adjusts to match the misregulated main inhibitory neurotransmitter GABA

Keep in mind that low pregnenolone sulfate has not been replicated in anyone else yet. Also keep in mind that the exact imbalance that could results due to having low pregnenolone sulfate could be different then my proposed mechanism. I’m simply going with the most logical outcome of outcomes that could in theory result from the lack of negative allosteric modulation of the GABA receptors.

I think the lab may send a test to the UK. I will find out and let you know.

4 Likes
#23

Ok I follow your theory - makes sense and thanks for explaining. Certainly in line with my original line of thought.

Please do let me know about test availability in the UK, I am very interesting at exploring a deeper level of testing vs what you can infer from simple bloodwork. It would be great to collect results from a wide number of PFS sufferers.

On a side note, I am glad you have mentioned that you crashed from SP. My hair loss continues to steadily progress and this is a good reminder to stay away from anything that inhibits 5AR at all costs!

Thanks again and keep in touch

1 Like
#24

An interesting finding indeed. Please keep us posted as you continue to delve into this.

1 Like
#25

We can just try low dose Fluoxetine for it.

#26

Scott,

You can order a test from the U.K. but you would need to pay for the shipping cost to have your completed test kit sent back to ZRT lab in the US.

You can order the test for $370 USD plus shipping . It’s discussed in detail in this thread:

#27

Thanks a lot for this.

I have just paid for a full blood hormone test here in the UK to be done. I will await the results (I have never actually had my blood hormones done before), assess my levels and then potentially look to get this done too.

On another note - as my hair loss has continued in the past years since I have been recovering from PFS, I have looked at other ways to address the hair loss problem at an androgen level and came across RU58841 (topical Anti Androgen). There is little literature on the substance as it is a ‘research chemical’.

However - I did a lot of reading into it’s mechanism of action and as I surmised that my issues were due to the upstream nerosteroid cascade we have been discussing in this thread, disrupted due to low 5AR levels and not due to a lack of androgens themselves, I decided to try it at a very very low dose. Stupid I know, although a calculated risk in my trivial pursuit of hairloss.

Used it for 2 days at 0.05% and it definitely created small episodes of PFS like cognitive symptoms. Now I am not a pharmacologist, however to my knowledge there should be no known interaction of RU58841 and the neurosteroids discussed here.

RU is a nonsteroidal anti-androgen. Meaning it binds to the AR without transcribing any effects and also has a very short half life (1 hour, whilst it’s metabolites have a half life of up to 20 hours).

I am saying this for 2 reasons:

1 - It is evidence to suggest that a disruption to androgen activity is at play here alongside potential neurosteroid issues. Albeit this is not in line with my original hypothesis.

2 - Topically applied solutions can still act systemically. I am sure we all knew this already, but even a very very low dose of this stuff clearly did have systemic implications in me.

Sharing as this may be a useful anecdote for the community and a reminder that we should avoid all anti androgens regardless of mechanism of action.

#28

Hi @Trazohell @5-alpha-victim @scott7777

I noticed you haven’t completed the patient survey yet. When you have some time, could you please complete it using the instructions in this video I created: https://www.loom.com/share/c298a179a0e64cba8ef9e69ae0122ac4

I cannot understate how important this resource has been when liasing with researchers and clinicians, and your participation would be much appreciated.

Thank you for your help.

Best,
Mitch

#29

@Sugarhouse

I completed the survey

2 Likes
#30

The studies specifically stated it worked on females and not on males. So it does something different in both male and female brains. I wish I was wrong but it’s what the study says. I’ve been trying it for a couple of months with zero progress and realize why .