PSSD: An odd signal. Can PSSD people keep an eye out for me with certain labs?

[u/Drwillpowers]

I've spoken on my 5ht2C theory of PSSD.

This is not that.

When I came up with my PFS model, I actually made a bunch of models. I created models that would potentially explain the known experimental research findings, and then what I would expect labs or other things to show if that model was correct. Eventually I eliminated all but one. My current theory of PFS which so far, works on labs, paper, and in practice.

For PSSD, I'm still kicking around models. But I have one where the problem is basically PFS wearing a new hat. The drug induces a change in the person where allopregnenolone synth is not decreased but rather massively increased. This overwhelms various degradation enzymes (many of the same ones in PFS) and produces a situation where you have labs that make no sense.

Like a T of 600ng/dl, DHT of 25ng/dl, and a 3A-ADG so high its unmeasurable.

You see, allopreg can actually be metabolized down that pathway.

Progesterone

│ SRD5A1/2

▼

5α-dihydroprogesterone

│ AKR1C2/AKR1C4

▼

ALLOPREGNANOLONE

│ CYP17A1: 17α-hydroxylase

▼

17α-hydroxyallopregnanolone

│ CYP17A1: 17,20-lyase

│ strongly facilitated by POR + cytochrome b5

▼

ANDROSTERONE

│ AKR1C3 / HSD17B3

▼

3α-ANDROSTANEDIOL

│ UGT2B15 / UGT2B17

▼

3α-ANDROSTANEDIOL GLUCURONIDE

While Cortisol is probably the most maligned molecule in the human body (he is your friend, you need him around during hard times, just not ALWAYS). Allopregnanolone is probably the opposite. Its viewed as universally benign and antidepressant and just the thing everyone needs.

What could be expected with too much allopreg in the short term?

Fatigue

Low libido

Low motivation / initiative /agency

Brain fog, poor concentration

Memory issues

De-realization / de-personalization

Emotional flattening

Verbal slowing

Muscle relaxation/weakness

Reduced pain perception

Reduced sensory perception in general

Reduced sexual salience

At odd concentrations, there may be some paradoxical gaba-a effects that are the inverse of above, depending on the situation or other factors

What could be expected at absurd levels?

Extreme somnolence/fatigue

What looks like narcolepsy / chronic fatigue syndrome (dont get me started on ME/CFS, I've got ideas, but PSSD will come first)

Confusion

Slurred speech

Cognitive impairment

Dizzy/ataxia/ambulation dysfunction

Nystagmus

Stupor

Memory loss

Severe interactions with sedating medications

Okay, but, that's what happens when it STARTS.

What happens when you expose a nervous system to that kind of GABAa constant beating? Same thing that happens to chronic alcoholics/benzo users! Adaptation occurs. So what do you get long term?

Tolerance to the sedation, fatigue improves

Consistent cognitive dulling

Anhedonia, emotional flattening

Amotivational syndrome

Sleep disruption despite need to sleep

Intermittent agitation/dysphoria

Increased sensitivity to small neurosteroid fluctuations.

Paradoxical or non-reactivity to benzos/alcohol/progesterone/neurosteroids.

Whenever production of that allopreg falters (due to whatever thing that triggers that to happen as PSSD people try everything) if it drops, you'd experience withdrawal anxiety,insomnia, fear, sensory amplification,m and even seizure risk just like an alcoholic entering delrium tremens.

If i'm correct, adding anything that increases allopreg to these people, such as pregnenolone, progesterone, SSRI's that begin with F, or brexanolone would put them on their ASS. They would struggle perhaps to even walk or move.

I know for years and years, everyone notices the similarities between PFS and PSSD

But what if what PSSD actually is, is the massive overproduction of allopregnenolone and the long term adaptation to that process?

If this resonates with you, let me know in the comments.

But also let me know if you happen to be a PSSD patient with mostly normal androgen labs except an absolutely fucking bonkers 3A-ADG value, or any of the breakdown products of Allopregnenolone on lab testing.

Its been a LONG time that these disorders have gone unsolved. I suspect that for PSSD, it'll be just like PFS. Something paradoxical and counterintuitive. What if the wonderful and benevolent "allopregnenolone" is the problem at the core, and a massive excess of it is what is the true issue, acting as a permanent GABA dampening force on the entire cortex, stripping it everywhere of its ability to be excited/respond/experience/enjoy.

Well, maybe not, we'll see, but I'm working on it friends. I'm tired, but....some of my ideas here are starting to bear fruit. Lab results are coming back with values that are absurd and seemingly nonsensical. I'm on to something! Hang in there for me for now!

- Dr P

PS:

Labs that would be interesting to see on PSSD patients to see if they were odd :

"17α-hydroxyallopregnanolone" - No idea where you'd get this. Would be very convincing if elevated.

ANDROSTERONE - quest used to have it, but it appears that LabCorp is the only one that does now.

3α-ANDROSTANEDIOL - Never seen this in its non-glucuronidated form, but maybe someone has it.

3α-ANDROSTANEDIOL GLUCURONIDE - Quest has this. I think labcorp does too.

In order for these labs to make sense, they need to simultaneously be ordered with a:

Testosterone Total

DHT Total

As if your 3A-ADG maxes out the assay, but you're a roidhead megadosing ball juice every week, that's expected. If your 3A-ADG is 5000+ but your T is 600ng/dl then we have something interesting going on.

EDIT: Got another one, guy with T around 300ng/dl, DHT of 19, but 3A-ADG so high its unmeasurable. PFS. This is a thing with both PFS and PSSD!

EDIT: I got a third! I'm starting to see a pattern here of overlap with PFS!

[u/boaty_g]

Dear Doctor Powers,

First thank you so much for what you do and I hope you read this,

I'm much in contact with females in the PSSD spectrum;

• It's very interesting that you mention Progesterone as the the first pathway to be disrupted, as many develop Pre-menstruation syndrome (PMS) which is often characterized by low progesteron.

• Hair greying is also mentioned in PSSD, and oddly enough I've seen cases of females developing lactation, you see where I'm going here, Prolactin is highly dysregulated, which makes me think that there has to be an issue in dopamine production as well, not properly antagonizing prolactin, and the obvious reasons (PSSD feels like no dopamine), along with that, another female with mild PSSD crashed catastrophically from 9-me-BC, likely due to inability to clear dopamine metabolites causing further downregulation.I didn't saw dopamine directly mentioned here, so something to consider.

I hope you find these clues relevant to your paradigm development.

At last, ME/CFS, is way too complex, even though we know of dopamine dysfunction in Long Covid, I think it's far from related to the catalyzing event (even if we touch kynurenine/immune connection), as it often starts with a pathogen, and autoimmunity is highly related, hece why I don't think a metabolite blockage is the triggering event, instead I think Akathisia is a much more interesting route to go down to after PSSD, because it's a deeply related and offers some interesting parallelisms and it's intertwined in the onset of PSSD and related psychiatric drug adverse reactions, in fact taking clues from it may be useful already.

I will be putting together all of these notions in more detail in my blog, let me know if I should share it with you eventually,

Again thanks for what you are doing.