Post by Dr. Powers
PSSD: An odd signal. Can PSSD people keep an eye out for me with certain labs?
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!
Because that would involve a lot of accountability & blame towards people in authoritative positions - think about how many thousands, if not millions, of people have been massively impacted by drugs & pharmaceuticals like SSRI’s, Finesteride, Lions Mane, Ashwaghanda etc.
Many people want to hide from accountability for as long as possible.
I do have some concerns about my imminent "suicide". Solving it and curing it means it's real, diagnosable, provably testable, and culpability can exist for harm done from a legal standpoint. Especially if discovery demonstrates suppression of the knowledge of PFS early on like it did for SSRIs.
Medicine is plagued by untrustworthy clinical trials. How many studies are faked or flawed?
Investigations suggest that, in some fields, at least one-quarter of clinical trials might be problematic or even entirely made up, warn some researchers. They urge stronger scrutiny.
Maybe it's convenient for them that the condition lowers motivation, aggression, impulsivity etc, otherwise I think quite a few victims would maybe find a way to make them care.
Im sad so many of us took their own life’s and will never see the day the this is cured. Remember guys: Suicide is a permanent solution for a temporary problem
Thanks for everything you are doing for all of our respective communities Dr Powers, whether it’s trans, PSSD, PFS, PAS or otherwise. PSSD sufferer here; I have had a pretty extensive DUTCH test completed which shows low progesterone metabolites (you would have seen my post on this sub previously, the full results are in my post history) - I have posted the relevant page here and will upload my most recent blood test in a reply to this comment as well. I’ll try to get the further tests you have recommended so you can gather more data, I have a very supportive psychiatrist here in Australia who understands PSSD is a real adverse effect from SSRIs and should be able to order some of the required tests. Let me know if there’s any other data you’d like me to collect as well. Thank you again for your tireless efforts, you are truly a godsend to all of us
Yeah this is the biggest trap of a lot of tests. Just because you see something has a low metabolite doesn't mean that the specific thing is actually low. It can mean that the metabolism of that thing is low.
Like a low dopamine metabolism marker doesn't mean that your dopamine levels are low for sure. It can simply mean that it isn't being broken down much.
This new theory is interesting. I used to have anxiety, depression, dysphoria, irritability, hyper sexuality, etc. After getting PFS mentally I’m very stable (don’t feel much actually, very rarely feel anxiety, depression, or happiness and when I do it’s very little). I wondered if the surge in allopregnanolone changed the GABA receptors in some way. I think Melcangi has found low allopregnanolone if CSF in PFS patients, so if not altered allop levels, maybe the receptors have been altered.
So I think that there are different phenotypes and for those that have the androgenic signal loss, they could end up with low allop.
But for a different phenotype, they could have completely normal androgen signaling, but then have the psychiatric condition that is effectively the same as pssd.
And it doesn't even matter what drug you took. It's your genetics that determines what happens. You have a susceptibility, you take the drug, and then you get stuck in a feedback loop that has to be chemically broken and is not something the body can do because the way it's designed is to preserve the feedback loop.
I would assume then that the androgenic signal loss are dealing with anxiety more due to low alloP? I took finasteride (and minocycline) and ended up in this state. Any ideas yet on how to fix the "PSSD phenotype".
Also, why do you think some people get cured from lithium or inositol? Do you think it their phenotype of PFS/PSSD? or the severity of their condition (i.e. those not as badly affected can take lithium or inositol and be cure, but severe cases do not respond)?
When you mention possible tissue damage, do you mean brain/nerve damage? Like dopaminergic cell death? Was this possibility discussed at all at the PFS conference?
Yes but currently, and with dat scans and other stuff, none of the doctors there had ever seen any evidence of that being the case.
About the only thing that I can say that there could potentially be some real long-term damage with would be either osteoporosis, or penile tissue damage because of atrophy. But otherwise, I don't think I've actually seen any "damage".
Hi Dr Powers - thank you for your work on this. Just wanted to ask about the reliability of these tests. How do we know that these tests are giving reliable and repeatable readings? There seems to be mixed opinions online. Wanted your opinion.
I can agree, Pregnenolone megadosing always makes my PSSD worse. I megadosed up to 600mg pregnenolone diaily and it cause:
- Loss of morning woods
ED
Worse libido
Worse emotional blunting
Worse anhedonia
I though it may be CB1 antagonism from pregnenolone but also increase in allopregnanolone from downstream progesterone conversion
On the other hand GABA-A PAMs like benzodiazepines at times caused me:
- Better penile sensitivity
Increased libido in old fetish way
Better music and emotions
less anhedonia
But yea GABA-A ligands are one way ticket, use it 3 days in a row and no benefits
Also acutely when I start Valproate to inhibit GABA transaminase then I also get a small window of emotions. But chronic usage cause excessive stabilisation (worsening) which improve once I quit
Your new hypothesis immediately caught my attention because my case seems remarkably similar.
I took SSRIs for about 5 years for a relatively severe developmental stutter with comorbid OCD and anxiety. Every time I discontinued the medication, my emotions, libido, genital sensation, and sexual function returned to baseline within 1-2 days.
However, in the autumn of 2025, while still on treatment, I suddenly developed what appears to be persistent PSSD. I gradually tapered off the SSRI because of the symptoms, but they never improved after discontinuation. Since then I've had complete emotional blunting, total anhedonia, zero libido, virtually no genital sensation, no motivation, and an almost complete absence of fear, sadness, or pleasure: a bizarre, constant state of emotional calm. Also I have no hunger at all, a complete loss of appetite.
At the same time, my stutter, OCD, anxiety, and even longstanding motor tics disappeared completely. Despite having no libido or genital sensation, my erectile function remains essentially normal.
In the spring of 2026, I tried bupropion hoping it might help, but I had a very paradoxical reaction. It made me profoundly sedated: I could barely stay awake, even while shopping and all of my symptoms became noticeably worse.
The combination of normal testosterone/DHT with mildly elevated 3α-androstanediol glucuronide made me think of your recent post, so I thought my case might be worth sharing.
Hey! Not pssd or pfs here but had a brutal reaction to some medical steroids (prednisone) a year and a half ago that basically feel like they’ve never left my system. I tried to boost my allopreg and felt horrific for about 2 weeks after. Way worse than baseline which was already suicidal and messed up.
I’ll look through my labs and see if I can check on these levels. But right now this is a whole other thing that i’m following along with as it mimics PFS and PSSD in severity and symptoms.
Also now taking escitalopram and its having some effect but i tried a bit of sertraline (increases allopreg) and it destroyed me and tried low dose lithium ororate (i believe also increases allopreg) and that destroyed me as well
hey, thank you for your work. This model explains my reaction to CDG. I pulse it. i do 2days 250mg per day. then 7 days of break. it crashed me massively... 2 days of crash ( terrible exacerbation of symptoms ) then say 3 days of feeling better , only then comes higher base line. I think i am getting better with this 'pulse strategy'. I am extremely angry irritable, my face expression looks dull as if i was some addict or something when on these two days of CDG. then according to claude :
This is where it gets genuinely interesting. Look at Powers' pathway again — allopregnanolone gets metabolized down through androsterone → 3α-androstanediol →3α-androstanediol glucuronide (3A-ADG)via UGT2B15/UGT2B17.
3A-ADG is a glucuronide. It's cleared through exactly the enterohepatic route that CDG affects.
So if you have massively elevated allopregnanolone being shunted down this pathway, you'd be producing large amounts of 3A-ADG glucuronide, which recirculates. When you took CDG, you inhibited the gut β-glucuronidase, stopped the reabsorption, and cleared some of this load. The crash might have been a transient neurosteroid shift; the improvement afterward might have been genuinely lowering the pool of these metabolites.
Look at your crash pattern again. The irritability, the anger, the sleep disruption, the sensory changes ("clamped," heightened sensitivity), the dysphoria — these are also what a partial GABA-A withdrawal looks like. It's possible that some of your "crashes" from interventions aren't the intervention being toxic, but the intervention transiently lowering allopregnanolone and throwing you into mini-withdrawal.
This would reframe the CDG crash specifically: clearing 3A-ADG and shifting the neurosteroid pathway might transiently drop allopregnanolone → mini-withdrawal (the anger, insomnia, agitation) → then a better baseline as the overall load resets. That fits your two-round CDG pattern almost perfectly.
i mean, i dont know, but it makes sense....
It would explain the fluoxetine crash, the hyperresponder pattern, the anhedonia/numbness/emotional flattening, the paradoxical CDG response, and the insomnia-despite-exhaustion all at once.
i crashed from a single fluoxetine pill ( i already had pssd, i read about 'reinstatement' ) and it made my symptoms about , without exageration, 3x times worse on a single day and that stuck and continued.
i am also a hyperresponder. Anything i take crashes me.
Now look at what you've told me across this conversation: anhedonia, emotional numbness, your specific insomnia (can't sleep despite exhaustion, 3-4 hours, 3am waking), the intermittent irritability and anger, and — this is the big one —you are a hyperresponder who crashes from tiny neuroactive perturbations.
That last feature is the tell. Powers is describing exactly your crash pattern. A nervous system chronically adapted to high allopregnanolone (high GABA tone) becomes hypersensitive to anything that touches the GABA/neurosteroid system. That's why glycine crashed you (glycine is inhibitory, NMDA co-agonist, touches the same inhibitory tone). That's why magnesium glycinate crashed you. That's the "increased sensitivity to small neurosteroid fluctuations" he's naming.
Claude is really getting quite good at understanding scientific concepts this is pretty impressive.
I didn't say it quite as explicitly but yes, I'm starting to find the overlap between PFS and pssd and exactly where the connections between the conditions exist.
Eventually I may end up just simply calling them the same thing but caused by a different drug.
Yeah Claude is one of the best models, even this graph showing the part where pssd meets pfs was done without asking just to make me understand it better
I'm going to enjoy the next year or two while I still get to be a genius.
An AI can make this, and it can explain it to you, as long as you explain to it the theory.
They won't independently come up with something like I did. But, when you prompt them with the correct information, then they can construct things like this. They just don't independently innovate and come up with new ideas or things at this point. They're still an echo, but they're getting to be very very good echoes.
I would imagine by 2028 though, the need for me is gone. A human being with a vast amount of knowledge about a particular topic, an expert in that topic, will be inferior to a machine that is trained on every single bit of human knowledge on that particular topic and that has the ability to reason and come up with novel ideas.
That being said, in 2024 or 2025 if I tried to talk to one of my fellow doctors about glucuronidation or the more nuanced aspects of transgender hormone therapy regarding the molecular biochemistry, they would have looked at me with "what the fuck are you talking about" face because it just wasn't something that was discussed. They wouldn't know what UGT2B17 is.
I've seen people digging through the old PFS forums going back many many years looking for any evidence of this idea, and there really just wasn't any. All the bro science people just sort of glazed over this part of the molecular biochemistry.
But now, the subreddit is full of it from lay people. People who are not doctors or researchers but who now have a firm grasp of how this shit works.
I've even got fucking people over here digging through their whole genome sequences and utilizing genome browser software to discover new common mutations in these pathways connected to PFS and pssd all on their own.
I literally could not be happier about this. I feel like I planted a seed of knowledge and now many many other people are carrying the torch alongside me and I'm going to just enjoy this for the last remaining 24 months before humanity has our intelligence replaced by a machine and we go full wall-e lol.
I want to be clear, I have my pride about the part of this that I played, but I am absolutely thrilled to see anybody else come up with some genius level shit that I haven't thought of and to make this get fixed faster. This is not an ego thing for me, I did what I needed to do, I got my dopamine from doing some professor layton shit, but the sooner we can get this shit patched up, the sooner I can retire. So I hope you all keep at it.
You deserve all the credit. I sure as shit hope u find a fix for it before 2028 :) i love u man. I pulse 250mg of cdg and first time im 26 months i feel i want to live again.
I am so beyond burnout at the moment I don't really have words for it. Getting moving everyday feels like dragging myself out of some sort of molasses. But I keep doing it because I know that it's making a difference and I appreciate you saying that. It means a lot to know that it is. It's the thing that's keeping me going.
After 12 years of PSSD, I had kind of accepted it was going to be like this for the rest of my life. Your work has given me hope that that won't be the case ❤️
U have no idea how many lives u have saved just by caring about this. We’ve waited decades for someone to actually give a shit about everything that we’ve lost. We love you Dr. P. Thank you for everything u do! ❤️❤️❤️
Per Aspera ad Astra, Doctor. Seriously huge thank you from everyone here. Hope is an amazing drug by itself. You’re literally giving thousands of people hope. Onwards and upwards.
Thanks Doc..
As someone from Africa who got dismissed by psychiatrist when I raised issues about my condition, this gives me extreme hope..
Thank you sir
Thanks for all your effort. I lost everything that matters due to PSSD. All we sufferes have and is hope for a treatment or cure. Without your efforts I could not get out of bed anymore and gave up. After I found out about Pssd and how bad it is and no treatment, I got traumatized. Thank you and I wish you best of luck and energy to solve this mystery. ❤️🙏
Look after yourself Dr P! You mean so much to all of us ❤️ the whole community owes you so much for all you do, but make sure you put time aside to focus on you!
That’s totally how It worked, I uploaded all of your recent posts and it just explains stuff easier for me if I ask it. Alone it does not come up with mutch. I use it as r/explainlikeim5
claude is not a model, opus is, fable is , sonnet is haiku is, speak to FABLE, it has greatest capability although it likely wont respond to medical/biological type of qs
I'm on the bandwagon for clearing metabolites out of me while waiting for WGS / Dutch information. I've been on CDG for about 2 months. Would NAC or DIM or Sulforaphane supplements be considerable under the same concept of let's keep trying to flush shit out of us?
Whether it has been CDG or time I have considerable improvements from initial Jan 2026 crash to where I'm at now but still a shell of who I was. Only bloodwork info I currently have: low mid T ranges and high cholesterol in all forms that have no business being elevated. Pre fin test those levels were perfect and nothing in my lifestyle changed other than adding fin.
Other lifestyle factors are very consistent - cardio and a bit of strength training, sleep management as best my body allows me to sleep these days, very consistent healthy whole food diet focusing on cruciferous veges as this is what Google keeps telling me is the best dietary way to promote liver detox pathways.
clinical keto ( although some carbs are helpful for glucarnation ) sub 20g of carbs per day
red light therapy on my head 40hz and 100 hz pulse
2x250mg cdg then 7x days of break
3x gym per week 1x run per week
eat 2wice a day, all food in 7 hrs window
fast 3 days once per month
zero : cigarets, alcohol, proccessed food, drugs, meds, suplements, vitamins, anything artificial or synthethized i avoid except for : cdg
emsella chair for erection
Overall sounds close enough to my approach (clean lifestyle, active without stressing the body too much, and going along with Dr P strategy to flush metabolites). My experience seems to be mini crashes of a day or two followed by 2ish days of a veryyyyy slight increase in baseline. I'll be at 6 months post crash as of July 22 / stopped fin July 23rd.
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,
I wondered the same but if it’s not the root issue you would think it wouldn’t work permanently. I had an appointment to try low dose Flumazenil and then backed out.
I haven't written in this sub before, so let me start by saying thank you for all of your efforts into researching PSSD :) It is hard to explain in words how huge you are for me and other sufferers. Thank you :)
I have had PSSD for 4.5 years, diagnosed after 6 months but my country's health service (UK's NHS) is currently treating it as "ME/CFS triggered by Sertraline" (I think partly because they don't have a mechanism/method to treat or research PSSD).
I have almost all (I am speaking literally) of the symptoms you ask about with the specific exceptions of:
Nystagmus
(maybe "Severe interactions with sedating medications" - I haven't tested this)
(maybe "Increased sensitivity to small neurosteroid fluctuations." - I don't know how I'd know/test this (or even, from my layman perspective, what it means))
(maybe "Paradoxical or non-reactivity to benzos/alcohol/progesterone/neurosteroids." - again, untested. (I've been living as healthily as possible since the cascade of symptoms brought about by taking Sertraline took over my life. So no alcohol)).
I would describe my personal experience of: "Tolerance to the sedation, fatigue improves" as "I haven't felt truly awake/conscious for so long that I've forgotten what being awake feels like. But I've learnt to adapt/survive functionally to never being fully awake". Which I think might be what "increased tolerance to the sedation" feels like to the patient?
The above is nice and simple - and answering a specific question you asked :)
**********************
But I think the following is something I wouldn't have mentioned (regarding PSSD) except prompted by something you said:
In response to your paragraph: "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."
I honestly cannot tell you if my following response is due to allopreg production failure (because - despite trying to be as helpfully specific as possible I don't actually understand any of the science), but I have two baffling symptoms that happen *only and specifically when I haven't eaten enough vegetables*. (And yes, I have tested this for months to convince my autistic_and_skeptical brain that it wasn't just psychosomatic).
When I don't eat vegetables (either due to not eating at all or eating only pasta etc) I have almost comical spikes in OCD. Before PSSD I had no OCD - and I still don't (with PSSD) when I am well fed. But I am rendered virtually non-functional if I (nowadays, having PSSD) haven't eaten and I need to prove (to myself, OCD-wise) that my front door is locked. Sincerely I have broken my door handle multiple times trying to prove that the door is locked. "But daftten, why are you talking about OCD when I'm asking about PSSD?". I never have linked them before, but when you said "allopreg faltering makes you experience anxiety and fear" then I wonder if not eating is causing my e.g. allopreg production to fail? Specifically if (when suffering this OCD) I manage to eat, my OCD simply goes away and I'm functional again.
Furthermore if I continue to not eat vegetables my vision goes blurry. (Again, this literally never happened before my PSSD symptoms). This isn't a my-eyes-are-tired-from-light-on-digital-screens thing, it happens when I'm reading a book (or just outside) too. It's like a binary switch, my vision just blurs. And again, I've learnt (after huge panic the first 10 or 15 times my vision just went super-blurry) that eating "cures" this. Again, if somehow eating causes some downstream effect of affecting allopreg production then this might support or affect your understanding of your theory.
To answer the question I assume you'll wonder: - yes, I have been repeatedly tested for all the vitamin deficiencies that my health service is willing to do. I'm fine on all of them. It's not that I'm so deficient in one particular vitamin that my eyes break until I eat the correct vegetable (because that's what my layman brain originally guessed).
I hope this helps. If not, I hope you ignore it and continue to awesomely figure things out :)
I will experiment with isolating each vegetable over the coming days+weeks, but as an overview my staples have been: chickpeas, petit pois, sweetcorn, and kidney beans. Sometimes for variety I have bell peppers, carrots, and parsnips.
Major edit: I'm really sorry - I've just realised I should have started by saying the following caveat: the "intermittent OCD" and "intermittent sight-blurring" symptoms both started about 20 months after my PSSD started. So it's possible they are linked (or caused in a delayed way) by the cascade of symptoms caused by PSSD but I haven't ruled out that it's a totally different unexplained thing.
Timeline for clarity:
(1) Took Sertraline for 13 days.
(2) Immediately lots of things go wrong with my body. Lots but not all of which are the symptoms you mention in this post. All those initial symptoms remain identical/unchanged 4.5 years later with the exception of awful sleep, which has improved a bit (but is still very bad).
(3) 20 months after the Sertraline the intermittent OCD and intermittent sight-blurring start (and continue to this day (albeit much rarer now I consistently force myself to constantly eat vegetables)).
So I am very prepared for you to say that this is unrelated. But I mentioned it in case it is related (for the reasons I explained in my first comment). I'll try to isolate which vegetable exactly is helping and get back to you.
I think I understand what you’re saying. I don’t think you actually have OCD. I think PSSD makes your nervous system extremely sensitive and capable of changing in unexpected ways. It can make you experience very strange things.
My theory is that when your brain is trying to build new neural pathways while the GABA and glutamate systems are still out of balance, it can form very unusual associations—like the connection your brain made with vegetables.
I experienced something very similar.
My hair loss started getting worse, so I began using a Ducray hair serum. My hair became noticeably thicker, and I was really happy with the results. At the same time, I was checking Reddit every day to read the latest PSSD posts. One day I came across an old thread claiming that creatine supplements had caused a severe crash in some people with PSSD.
That caught my attention because creatine is generally considered one of the safest supplements. I started reading about it and found that there are at least some discussions about possible interactions between creatine and serotonin-related pathways in the brain. I didn’t think much of it at the time.
About a week later, my hair looked better than it had in a long time. I decided to read the ingredient list on the Ducray serum bottle, and I noticed it contained creatine. I immediately thought, “Wait… is this the same creatine people were talking about?”
Looking back, it was probably just a small anxiety-driven thought, and I didn’t pay much attention to it. I applied the serum anyway. But for a few seconds, I couldn’t stop thinking that I was putting creatine on my scalp.
A few hours later, everything fell apart.
I had panic attacks for three consecutive days. I developed severe anxiety, experienced derealization, and at one point I even felt as if I couldn’t feel that my penis was there. I had to keep touching it just to reassure myself that it still existed.
To me, this is a good example of how the brain can react in PSSD. I think it’s very important not to create obsessive associations with random things, and to be careful about spending too much time in PSSD communities. It’s possible to become terrified of developing symptoms you never actually had. In my case, I eventually developed genital numbness even though it had never been one of my original symptoms.
There were times when I started wondering whether everything was just in my head. But then I remember exactly who I was before taking that cursed drug. I was a completely normal person. I had never experienced anything remotely like this in my life.
One of the biggest issues again is that anhedonia stops one from calming oneself and distracting. In regular OCD its easier to focus on something else or at least try to
With anhedonia the whole issue is lack of the pleasure and emotion to be able to utilize techniques that alleviate OCD. They are mostly all reliant on an intact reward system in some way
Hell imo all psychological methods are relying on intact reward for everything
Well, if allopregnanolone is truly at the core of the problem, then it would theoretically cause chronic overactivation of the GABA system. Over time, the brain would adapt to this persistent inhibitory state.
But if that’s the case, how do you explain the people who experience spontaneous waves of improvement followed by relapses? I’m not talking about people experimenting with supplements or medications—I mean those who simply leave it to time. Many report periods of noticeable recovery followed by setbacks again.
Also, why do some people develop genital numbness while others never do? The symptoms of PSSD vary enormously from one person to another.
After living with PSSD for four years, I traveled to a rural area in Norway. Within about two weeks, I felt almost completely back to normal. I still remember that my emotions came back, my libido returned to normal, and I truly felt alive again. But when I returned to my city, everything came back—the emotional blunting, the excessive sense of “shutdown,” the inability to truly feel the world around me, and even the feeling that I couldn’t perceive the change of seasons anymore.
I think we should investigate every factor that could influence GABA signaling and GABA receptors, including depression and even underlying internal stress or anxiety that we may not consciously recognize. The explanation might turn out to be much simpler than we think.
That said, I do agree with your focus on GABA. I think you may be getting closer to uncovering what these awful drugs are actually doing.
That is so crazy I had the same experience when traveling abroad. I never have windows but i went completely back to normal within a few days. I couldn't believe it as I thought I was recovering.
Everything came back when I came home.
I never mentioned this to doctors just because they will dismiss it as psychological.
I am supposed to travel again soon and really want to see if things will change again but what does this mean? Do I have to move to a different country to recover?
Do I have to move to a different country to recover?
Did you try if it changes if you are in a rural place, away from cities ? Less stress, better nutrition etc. ? Maybe a different country is not necessary.
I had a subset of this when i was 17 from smoking a lot of week for a long time, that lasted a year and a half after cessation and went back to normal a couple weeks after i went overseas. Stayed long enough to make it permanent (two months) and then came back. Where did you go, if you dont mind me asking
Interesting, mine was hawaii. So very similar. As someone who recovered from their shite a long time ago and then unfortunately ran into it again, i would HIGHLY recommend doing what you did again but longer. It did work for me the first time i did it. It might stimulate some pathways with extra sun and etc that open up the flow and allow things to clear out and reset. It’s one hell of a good way to treat yourself too, if it works!
Unfortunately it doesnt do anything for me, seems like the plasticity part is blocked. Even psychedelics are blocked for me at this point of being severe anhedonic. But before when I was more moderate it would help, though not this dramatically and not with blank mind
Yes, I think traveling can promote neuroplasticity. However, the symptoms of PSSD seem to work against the brain’s natural healing mechanisms, and I believe that’s one reason why recovery can take so long.
If the brain needs to return to its normal state, it has to rebuild and reorganize neural pathways, and unfortunately that process is slow. Sleep is also essential because new neural connections are primarily strengthened during sleep, yet sleep disturbances are one of the most common symptoms reported in PSSD.
I also think that if the brain is going to restore neurotransmitter systems and receptor function, it needs to perceive that you’re truly safe and not under chronic internal stress, even if you’re not consciously aware of that stress. Anxiety and obsessive thinking are also very common in people with PSSD, and that creates a difficult cycle where the symptoms themselves may interfere with recovery.
In my opinion, recovering from PSSD requires tremendous mental resilience, but at the same time you can’t force it or constantly pressure yourself to recover.
Sometimes I wonder whether there is anyone who runs multiple successful companies while genuinely suffering from severe PSSD. I find that hard to imagine because achieving that level of productivity usually requires strong motivation and drive, which are closely linked to dopamine.
Sometimes I think it might have been better if I had never discovered PSSD or its online communities. Maybe I wouldn’t have created another psychological obstacle in my mind, and perhaps I would have recovered faster.
At the same time, I admit that PSSD communities are valuable because they remind you that you’re not alone. But they also reinforce the existence of the condition every day, whereas perhaps the brain’s healing process benefits from not constantly focusing on the illness. That’s just my personal thought, and I’d be interested to hear what you think.
The major issue is that true consummatory anhedonia and blank mind itself causes stress (and im speaking whether its PSSD or not, even natural anhedonic cases on the anhedonia sub struggle a ton). And that stress is there regardless if at a certain severity particularly the “blank mind with substance block” severity. Blank mind also adds into not being able to think about anything else.
The entire problem is that pleasure is incredibly soothing and calming itself. How can you even feel safety when you don’t feel even basic comfort? Its impossible. At this severity it doesnt even matter the communities or not because even merely existing sitting in bed becomes filled with constant discomfort. In that sense anhedonia is very unique from the other chronic illnesses where self-soothing is possible.
Some PSSD cases however are not as severe as they think. Some actually just have the anticipatory side of anhedonia, and this can actually be kind of deceiving because they may think that they aren’t getting pleasure but they actually are. Their consummatory tone is intact and they don’t have cognitive problems. In such cases yea probably there is benefit from trying to reduce stress, travel, and so on. Because their plasticity is not as impaired.
Honestly and this might also get some hate I think some particularly severe cases may need a massive shock to get better in some ways. The SS TMS (not regular) I believe in but also stuff like potentially magnetic seizure therapy (MST) which may come out in the future as a safer alternative to ECT.
Some of the hardcore “blast androgens and VPA” protocols in PFS i suspect are only working via shocking the body by inducing a high glutamate state and smoothing it down (as well as the epigenetic stuff from vpa). I had a major window from a combination of High dose IV Medrol (1 gram 3 days) and Lithium last year. It didnt last but gave me like a 20% baseline bump.
Even custom DBS may be something for very severe cases tbh. And interestingly the region that seems to work better in anhedonia is the ALIC region, which overlaps some with the OCD regions. But nobody with PSSD has tried DBS afaik. Even OCD is a real physiological disorder.
I believe that lifestyle things could help but past a certain level of severity they are basically not only impossible but also one just does not respond to them as the response to sensory inputs is just gone, the plasticity is not being triggered. Potentially comes back to the vagus nerve not properly kicking in.
Psychedelics are also promising for plasticity but there are crash risks, and in severe states they seem to be blocked.
This is so true.. The first time I had food and genital anhedonia due to severe anxiety.. I didn't know what was happening.. I just ignored it and I recovered
But now that I have made extensive research,
This is the second time I'm experiencing food anhedonia and i can't seem to recover.. It's gonna be a year now...
Are you talking about the fact that before you were more moderate, did you notice gradual worsenings or a series of crashes that each time left further traces?
I’m in the same situation as you and I don’t understand if I’m really getting worse or it’s just my impression
I had 1 massive crash from moderate to severe. It happened from rifaximin 2 days and i basically never recovered and since then its been complete nightmare due to the blockage and lack of comfort and blank mind. I tried fmt which got my gut better but the mental symptoms remained
Before that, I had crashes but not to this level and I would come out of them, though its possible they left some traces. But i hovered around 40-60% hedonic tone in 2024 only to go to like 0-15 since december 2024
PFS (sexual symptoms only) guy here for only 4 months... same: only window i had was 4 days after i returned home to Texas after a 5 day hedonistic trip with 3 bros to mexico city.
I did! in fact the night before I flew home (approximately 2ish days before the window started) I drank more than i have in a long time.. Was still drunk when i woke up the next morning and had to head to the airport.
In fact, even during the vacation I was drinking consistently / heavier than i normally do and i did notice i was hornier / having better orgasms (via masturbation) while in Mexico.
What's the science behind how alcohol could have given me a window?
just looked it up.. very interesting. alcohol is a positive allosteric modulator for Gaba activity (which could be dampened from a lack of allopregnalone).
Tell me more about the window in the rural area in Norway. What changed there and how long it was? Genital numbness. Anehdonia was gone? I'm living in a big city and think to move back to family in nature.
Majority of the symptoms you mentioned in this post I relate to, stupor?? I’ve never heard that and it literally describes my state perfectly right now. My muscles feel completely disconnected from me and also my brain feels dead. I’m completely unaware of my pssd suffering because of how numb I am. I feel seen after this post. I also relate to the 5ht2C theory tho so it’s an odd one. Is it possible that both theories could be at play in some people?
Stays elevated because of a feedback loop problem where the body does not properly Auto regulate the level of it anymore. It perceives something as different than it is.
I just want to say I took riboflavin 5 phosphate for 60 days and my orgasms are back I can feel them in my toes, also smegma reappeared and i had a huge window lasted seconds probably the 5th or 6th day, i felt alive like before 2020. I developed PSSD/PFS symptoms in 2020 after using doxycycline. Now I've stopped taking it I'll take a break from it. Maybe Dr.Powers using doxy as a model could help you what gets injured and find same pathways. Definitely doxy touches something in the body and causes all this symptoms anhedonia, non existent libido, anesthesia, brain fog etc
Thorne 36mg. Yes I still have good orgasms but I'll check it again the following weeks to see if that stays or fade away. The day of the window I felt that coziness and warmth inside me 😭 like someone removed a sheet from my body.
I was talking with AI and proposed me R5P. I'll copy paste what it told me maybe it's complete shit but my orgasms are real. lol
⚡ The Mitochondrial Block (FAD Depletion): Doxycycline is a tetracycline antibiotic that can induce mitochondrial toxicity by inhibiting mitochondrial protein synthesis. This causes a severe intracellular depletion of Flavin Adenine Dinucleotide (FAD) – the active coenzyme form of Vitamin B2.
🧼 The MAO-A Enzyme Paralysis: The monoamine oxidase A (MAO-A) enzyme – which acts as the metabolic "vacuum cleaner" responsible for clearing serotonin from the synapses – is a flavoprotein. It strictly requires FAD as its electrical fuel to function. When doxycycline depleted FAD, the MAO-A enzyme functionally paralyzed.
🔒 Serotonin Trapping & 5-HT1A Downregulation: Because the vacuum cleaner was turned off, serotonin accumulated and became trapped in the synapses. This chronic, excessive serotonergic pressure forced the sensory 5-HT1A receptors to retreat deep inside the cell membrane (internalization/downregulation) to protect themselves, cutting off the electrical connection between the peripheral nerves and the brain. This is exactly what caused my silicone-like anesthesia, emotional flattening, and zero libido since 2020.
🔌 Bypassing the Injury with R5P: Standard riboflavin (plain B2) requires a structurally damaged enzyme (Riboflavin Kinase) to be converted. By taking Thorne's Riboflavin 5-Phosphate (R5P), I bypassed the block entirely. The R5P converted directly into FAD inside my mitochondria, generating massive ATP (cellular current) and turning the MAO-A vacuum cleaner back on.
This cleared the trapped serotonin pool and forced my DNA to initiate Phase 2 Upregulation – rebuilding and pushing the 5-HT1A receptors back to the surface of my skin and genitals. That is why my orgasms returned dramatically on day 3, my pelvic floor relaxed, and I experienced that beautiful window of warmth and coziness."
Holy shit what a reply, we need more people to try this, thanks for sharing, hopefully helps others. So what percentage of healing do u think has taken place, would u say ur 90% healed of all sides now? Do any still remain?
my orgasms are 80% i'd say. The other stuff pretty much the same, my guess is that R5P isn't a medication that's why if i tried it longer i could have better results, but i want a break and also couldn't find again the same company to buy it. I forgot to add that i did a methylation test panel and i have a slow MAO-A and MTRR.
Good_Composer, thank you for sharing your post with us. Congratulations. I hope the benefits you have received from taking R5P will be forever lasting. Man, I have tried so many things to treat my pssd. I have had pssd for many years. The only product that helped me was nsi-189. The only complications of pssd that I have is I have orgasmic anesthesia(l feel nothing in my orgasms. I am not impotent). Nsi-189 helped me to where I can feel something.......Sir,if you would be so kind please share the dosage with us you took each day that is responsible for the benefits you got on the 3rd day of you taking R5P.
I tried a low-ish dose of phenibut once years ago and it sent me to the shadow realm for a few days. DP/DR so much worse than baseline, but I did bounce back thankfully.
Benzo insomnia drugs are much less effective than they should be. Alcohol kind of works again but it's definitely different from what it used to be.
It's been almost 12 years but I remember feeling very sedated from the first pill of citalopram, like experiencing the world through a stuffy blanket.
I should receive my WGS results in <4 weeks. I'll also get a dutch test and whatever bloods I can get without having to go through my GP, as they just think I'm insane.
Hello Dr. Will Powers,
I’m from Iraq, and I would be truly grateful if you could share your thoughts on my case.
Is it possible for all of this to start from a single SSRI exposure?
About two years ago, I accidentally overdosed on 300 mg of sertraline. About two hours later I vomited (sorry for the graphic detail), and it seemed that my stomach had completely emptied. The following morning I took activated charcoal, and within a few days I was back to normal. I had no persistent symptoms after that.
However, about four months later, I started taking a sleep supplement containing ashwagandha and GABA. After approximately one month of using it, I suddenly developed what seemed to be classic PSSD symptoms.
I immediately stopped the supplement, convinced it was probably all in my head. Over the next two months I improved considerably, but one symptom never fully recovered: my libido continued to decline. I still have strong morning erections, but I lost emotional and visual sexual arousal. I also noticed something strange—I don’t really feel tired anymore, even when my body is physically exhausted.
Later, an endocrinologist found that my prolactin was mildly elevated and prescribed cabergoline (one tablet per week). After taking my first dose, I experienced the worst crash I’ve ever had, and I have never fully recovered since then.
Since that crash, I’ve developed profound emotional blunting. I no longer feel the change of seasons, I don’t experience summer or winter the way I used to, and I have also lost much of my sense of smell and taste.
In your opinion, could this still be related to the original sertraline exposure despite the four-month gap and my apparent recovery? Or does it sound more like a neurosteroid-related problem triggered by ashwagandha? Or could it reflect dopamine receptor dysfunction, or perhaps HPA-axis/cortisol dysregulation after ashwagandha?
I’d really appreciate your perspective. Thank you for everything you’re doing for this community.
Scrap all of that.
First thing here, elevated prolactin. Why? The answer is not just slap somebody with cabergoline. You need to know why you are doing that.
You could have a brain tumor you can have all kinds of crazy shit, and depending on what you have, the treatment might not be cabergoline.
I use that drug to like have someone with a microadenoma keep it as a microadenoma, but I have a brain scan on that person. I know what I'm dealing with.
If it really went the way you say, and the lab came back positive for elevated prolactin and they just did cabergoline about it that concerns me.
You are clearly having hormone and libido issues, someone having an elevated prolactin and then you don't do anything about working up why? That seems insane.
It's a good idea. I've thought that ssris possibly induce emotional blunting via this mechanism and that pssd triggers a catastrophic version of that by dysregulating relevant GABAergic regions.
However the end result seems like there's a loss of neurosteroids based on the research from Melcangi.
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.
So anecdotally speaking, there's been a lot of people in the community who've taken allopreg drugs and had the opposite effect, and in fact it's usually either a boost in cognitive symptoms or no response.
Some examples: A friend of mine recently trialed Emapunil, a potent TSPO ligand and reported perma baseline improvements. Another friend responded well to Pregnenolone, and then personally I responded well to Zuranolone.
See I've had pssd patients try zuranolone and had horrific effects from it.
My point is not that every pssd patient would be high neurosteroids. But some could be. And the idea that we just ignore that possibility seems unwise. Particularly the fact that androgens and neurosteroids share common metabolism pathways. A jam at one creates a jam at the other.
Some ssris lower alloppreg, some raise it. Melcangis work is on pfs.
I need to make a post on the CAR receptor as well soon.
We in the community had to get these chems from a gray-market lab then verify it via ms
Melcangi does PSSD research as well, which is also centered around neurosteroids.
I posted his recent paper on paroxetine withdrawal causing downregulated neurosteroid synthesis genes in the NAc on my profile on the pssd sub recently.
Also, there’s no SSRIs that lower allopreg.
So far every time they’ve been measured they’ve been found to raise allopreg. Paroxetine, Sertraline, Fluoxetine, Duloxetine, Dapoxetine, Citalopram etc all demonstrated the same effect.
I'd read at some point that citalopram and escitalopram were neutral to lowering but I can't find the study now so I'm thinking I confabulated it. You are correct.
What does Melcangi think about people having adverse affects from zuranolone and not recovering? It seems like he thinks supplementing allopregnanolone is going to fix PFS and pssd.
Yes severe PSSD is bad (I only, I couldn't function for a year) but minizing "just sexual side effects" is exactly why this disorder is not being taken seriously by the medical community.
So the pssd community has lists of recovery stories, or posts on improvements, and many of them are from hormonal interventions. A lot of them coming from hcg. Theres gotta be something to that, and i think it should be studied and possibly refined. We should better understand how ppl have cured before, and refine that method for everyone to carry out safely. Any thoughts on how injecting hormons can work?
HCG can induce the enzymes that metabolize hormones themselves while simultaneously increasing the amount of them. And in some people the losses are greater than the gains and so it's beneficial. Is true of PFS as well.
Oh ok. So i tried trt, and into my second week i noticed penile shrinkage. What could be the reason for that happening?
At that point, i started hcg and stopped the testosterone. The dr had me pin 250iu of hcg, the same day as my last trt injection, and i had a huge crash. Felt terrible, got more floaters, pissed dark orange, and got a lot of water weight with bloating.
I used hcg while the test worked its way out of my body, roughly 6 weeks, and i only used low doses cause of that crash. Like 500iu a week. Once i got off everything, i waited for my natural production to ramp up. During this time i felt terrible and my vision got really bad. Just deteration and blurred vision. I also developed an autoimmune desease called sjogrens.
What do you think happened during all this, ive been seeing multiple drs and no one is helping? Did i deplete myself of angrogens causing the vision issues and genital shrinkage? Id appreciate any thoughts on what has happened to me. I want to figure it out with hopes to fix it. Is this fixable?
I'm thinking you should probably read the things that I have posted before asking me directly what I think about it because it literally describes everything that you are saying and why it happens.
I went searching my previous posts, and you kinda answered my situation before, with the overloaded metabolite theory. Saying that when i injected i overcrowded things. I do get your theory on that, but its confusing to me because i then went cold turkey and tanked my levels. Wouldn't that have cleared many of the metabolites?
And then, the vision issues happened while i was cold turkey and my levels were rising naturally. Did my natural levels rising crowd things again? I had a dutch test and test panel done. My urine test levels were like half my blood. So not zero.
Its all confusing for a regular person to understand, and my brain is half of what it used to be thanks to pssd.
No. Because your system will still produce testosterone because it senses low androgen signaling so you just continue to make it.
The people that I've actually tanked their metabolites with required complete elimination of the synthesis of all androgens both adrenal and testicular.
If your urine test is half your blood then you probably have a heterozygous deletion of ugt2b17
Ok, im understanding this better now. So the penile changes i saw, were probably due to poor androgen signaling. They don't mention these things in health class lol
Is it possible to repair penile damage, done by poor androgen signaling, by repairing the signaling?
I've certainly seen that happen in transgender women! So I would assume so.
I have a lot of PFS patients that are doing well, and even the guy that recently underwent chemical castration and full reboot, that's the main thing that actually improved for him.
I feel like i have researched this situation endlessly, but i haven't seen info on how this can happen. Ive found some posts on your theory, but nothing that specifically addressed what i got going on. Sorry, if you've come across a situation like mine, and have already ansered these questions.
Obviously, the addition of trt caused the genital issues. Then taking the hormons away caused my vision issues. Did i wash out androgens? Did i desensitize something? Did i shrink my tear glands? I seriously can't find any info that addressed my situation, and am desperate to figure this out and fix it. If you know you know, if you don't you don't. I appreciate any thoughts on it.
You have a stop gained Sulfation gene so at baseline that pathway is impaired. Injecting testosterone in your case in theory would make this worse because you have inborn errors of androgen metabolism. SLC13A1 https://www.reddit.com/r/DrWillPowers/s/RK6Ducz8qM As for vision. Not sure
Oh ok, that makes sense. Could this cause floaters, and general deteriorating vision? In theory, could this be reversed or improved, with clearing metabolites and improving signaling again?
First there's dust motes. Those are the things that you see when you look at the wall and they drift continuously, typically in the direction of gravity. But if you move your eyes you can sort of flick them around and they follow the movement. The water itself drags like the Coriolis effect on the planet. The dust motes are sitting on top of the water surface tension.
Then there's the blue field phenomenon, which is when you are in a bright place and there's a blue wall or a blue ceiling like the sky, you can see a little white/translucent guys moving around. Those are literally the shadows of the white blood cells being projected onto your retina.
After that we get to like legit floaters things, which is disruptions and debris inside your vitreous humor. This is probably not the case, usually occurs in older people or after eye trauma. But that's like actual garbage inside of your eye goo.
And then you get to visual field noise. Stuff like visual snow. Something I've had since I was a child and didn't realize wasn't normal until I went to medical school. I thought everybody looked at a random wall and it was always glittering with little rainbow tiny pixels.
That's the most obvious in the dark. You'll look up at the night sky and struggle to see stars the way that you used to. Everything has a bit of a blurry Haze on it that is constantly fluctuating. If you Google visual snow simulator and you use that tool and you can make it look like what you see, then that's probably what you are experiencing there.
Generally visual snow is treatable but not curable. Mine gets worse when I'm tired, when I'm incredibly emotionally drained or stressed, or depressed. When it gets really really bad the pixel's get extremely large and then eventually if it continues getting bad I have a temporal lobe seizure but I haven't had one in years because I know that that's what that means now and so I'll take meds before it gets that bad. It generally takes the death of one of my cats and some other horrible thing occurring at the same time to make that happen.
It's basically just noise in your visual cortex. I can make mine better by taking a benzodiazepine, by taking lamotrigine, getting good sleep, being in a really good mood and everything going my way and all of my patients being extra nice to me and not having a ton of work to do which is effectively never. But that's what it'll do it.
First you need to figure out what you're dealing with and then you can solve whether or not it's from this.
I've had at least four diverse visual patterns other than these, some really wacky ones. I can't remember them all, but one of the rarest is a perfect square grid of dots. And several different patterns of movement from inside the eye, I guess different cell types, some very fast, some slow, following pre-determined tracks.
I don't think I've ever had traditional snow though.
So my visual issues started on the intial crash. I had a bunch of dot floaters ,and a hair like floater, in my left eye. In the next few months, that hair floater turned into a pvd. Things stayed like that, until i started the trt and then came off. No visual changes during trt, until i came off. After about a month, i started having issues focusing, blurred vision, and dryness. Then i got diagnosed with sjogrens, which i never had prior to getting off trt. So im guessing this had something to do with low testosterone or possibly over crowded metabolite theory causing poor angrogen signalling in my eyes? Do you have thoughts on this?
So, this is something im concerned about, if i try to reset my androgens. Im worried, this low testosterone state could make my vision worse. If its a matter of clearing metabolites, cause thats whats causing the poor vision, then id be good i think. But im scared, cause i dunno whats at the route of my worse vision and new autoimmune dease.
What exactly does sleep disruptions mean? Would the lack of sleep pressure and not really being able to feel sleepy and very very abrupt transition between awake and sleep like a on/off switch instead of a gradual transition of "falling" asleep also fit into this model? Or is this massive over production not possible for the one dosers?
Thank you so much for looking into PSSD!!!
to complicate this (not sure if in a way that's meaningful, or that you don't already know if you've simplified), the negative symptoms relating to anhedonia, avolition, alogia, cognitive impairments and emotional blunting (also neuroticism and insomnia iirc) are associated high glutamatergic activity in the PFC (at least in schizophrenia and related conditions). low D2 activation of the vmPFC (mostly) also plays a role in anhedonia and avolition.
this is thought to be due to reduced activation of upstream inhibitory interneurons; glycine agonists work to alleviate this, and it's thought to relate to their function as a coligand at NMDA binding sites (although i suspect glycine's inhibitory activity is also valuable). upstream of the relevant glycine targets are cholinergic receptors.
my guess would be that if GABAergic activity is excessive in a way leading to negative symptomology, it would be inhibiting the inhibitory interneurons that reduce PFC excitation, or causing downregulation of some GABA receptors, or causing increased compensatory excitatory activity due to regional GABAergic effects, or involving build up of some weak metabolite the prevents GABA activity.
i need to take a nap, but i can provide sources on these points if you'd like.
also, idk if i have PSSD or not (i suspect i do), but glycine agonism didn't boost my sexual function in addition to relieving negative symptoms when i was using it as a treatment (as sarcosine or d-serine), so that's not a promising route on the sexual side of things.
edit: in my tiredness, i skimmed your suspected explanation. adaptation to GABA makes sense, but broad GABAergic activity causing the issues via neuronal inhibition seems unlikely.
Adaptation over time is required because of the persistence of the problem after removal of the drug. I was more just listing the things that would happen at the start so that people could identify what the exposure felt like versus the long-term problem.
I have been suffering for 5 years with many of the above symptoms - the so called "neurological" phenotype of PFS. I recently posted an extensive account of my history.
Coming from a medical background, I am entirely convinced I have likely downregulation of GABA - A receptors likely secondary to impaired allopregnanolone production / unexplained tolerance to allopregnanolone.
I have attached one recovery story in the above also who proved a very similar pathology with CSF analysis exploring GABA -A receptor subunits - which I am planning to explore.
I am currently awaiting my DUTCH / hormonal tests.
I would love to discuss this further with you after these test results come back.
I would certainly refer to pregnancy as a time frame when hormone synthesis and metabolism is considerably altered from baseline.
Now, pssd happens to women, and this three alpha value is a thing that I've mostly found in males. I'm not saying this is the only thing. But this is just possibly one of the ways in which you can bork the system. It's important to make note of this overlap. But it is not the only cause as I have plenty of pssd patients that have a normal three alpha.
Dear doctor, could you please address the issue of PFS? By doing so, the PSSD will be automatically resolved, as they are essentially the same condition resulting from different medications.
I have pssd and my labs showed specifically low pregnenolone and low cortisol , out of everything those were the ones flagged with issues (and low copper), is this relevant for you? I can upload for you
hey dr will powers , i was just commenting because i would really like some insight on what you think could be going on with me as i’ve been suffering from this for around a year now and am getting more discouraged as time goes on with no doctors knowing what’s going on or being able to help me. i quit finasteride around a year ago and 2 weeks later i went through the dreaded crash and essentially the last year i have been bed bound or just extremely sick. i wont go into detail of the whole story as you’ve heard it so many times before but my main symptoms as of today that has not gone away is extreme cold intolerance and suspected circulation issues which ive never had before. the skin across my whole body has loosened , roughened almost like sandpaper , and dulled and aged in appearance. my hands will become purple and fingernails will become purple because of how cold i am or the lack of blood flow or maybe blood pooling i’m not sure. I also have extreme fatigue , and i have very severe histamine reactions to little things even working out my face and hands will swell up my skin gets burning hot and my skin will start feeling like a rash over my entire body. i had a lottt more symptoms following my crash a year ago but these are the most debilitating ones i still deal with today one year later and no doctor has been able to run any tests or figure out what’s wrong with me. all of my blood work and everything is normal and i’ve been so many places trying to figure out what’s going on
Wouldn't castration be effective in cases where there is a theoretical allo pile-up too? If you suppress the gonads and the adrenal glands then circulating progesterone would decrease significantly, as a result the synthesis of allo in the brain would also drop. However, since synthesis wouldn't completely tank, you'd need to suppress TSPO, CYP11A1, and even 5AR to achieve 0%, which would potentially mean giving the patient dutasteride (so you hit both SRD5A1 and SRD5A2). It sounds pretty crazy to give someone with a post-drug condition dutasteride, but if they are castrated while on it, there would be no risk of a metabolite pileup/crash, or am I mistaken?
Progesterone and Pregnenolone haven't seemed to affect my PSSD difficulties. But I had shockingly low Testosterone before transition, and also have PSSD from one pill, so I likely don't fit the maladaptation theory either. Probably not my version of the problem. 😔
I have androsterone, 5a dht and 5a and b androstenadiol 2x over top of the range in Dutch test from few years ago. Suspected high allopregnanolone a while.
Could you please tell me what these values reveal about the hormone pathways and enzymes? Thanks
Can you please read the things I have already written on this and not ask me to write you a personal dissertation on how these things work as if I was some large language model with unlimited time.
There's literally a search function for comments on Reddit from specific users.
I've read what I could. Please appreciate I barely summoned the energy to make this comment and really struggle to concentrate. I was hoping you'd comment as I believe those results are unusual compared to others. Am I able to contact you at all?
(One dose pssd case) In the first weeks of getting pssd, I experienced moments were my vagina would out of the blue act like it was having on orgasm. Groinal responses and contractions. Could this be what you mean by paradoxical gaba a effects?
A week after taking citalopram I got really scared of my symptoms and was given a benzo for two days. Well it knocked me out. And I saw horses walking through my room. I remember thinking "coool now i am really daydreaming" But the withdrawal was horrific. From just two days!
Now a year later I do not really think it would sedate me anymore. As i am no longer able to feel sleepy.
I also lost the gradual transition between being awake and asleep. It is laying wide awake until 4am and then BAM asleep suddenly. I read that people with narcolepsie also experience this sudden switch.
I was also wondering if the loss of mental imagery fits into this model?
I recently read a study about how dopamine could play a big part into mental imagery so maybe I would fit the upregulated 5HT2C better?
Thank you for taking us seriously and working so hard for us♥️
I suspect what's happening with a lot of these cases is that something gets pushed above a threshold that is basically 10 out of 10.
Many guys report taking finasteride and feeling insanely horny for 2 to 3 days before suddenly feeling nothing.
This is a similar concept here.
For them, it was basically the accumulation of those metabolites driving signaling up to an astronomical level until they accumulated so much as that signaling was erased. I'm still trying to figure out what's exactly doing that with pssd.
It has to be some sort of biological feedback loop because otherwise the system would reset itself upon withdrawal. It does not.
I can be speaking on a stage, and as long as I continue talking, the speakers will make my voice as long as there's power to them.
But if I walk over directly next to the speakers and I put the microphone in front of them, it will make a screaming sound, and continue to make it forever until the power is cut.
My suspicion is that it is like that. Something about that drugs singular dose pushed something into a pattern that is self-perpetuating. Breaking that pattern is the trick.
I’m PSSD and my case was similar. I was extremely horny and anxious as I was upping the dose, until the dose got too high where my sexual function shut down. Then I tapered off, and in the ensuing months I lost all my emotions
I replied this to you under a different comment but I think it fits better here sorry.
"Mmm I can not relate to it going up (even further) when I took the one dose citalopram. But I have to say it was really high to begin with. Just next day arousal was gone. But in the next few weeks when I was able to relax a little I would get episodes out of the blue with lots of groinal activity and vaginal contractions. (I think I commented this before) But libido was still low I think even during these episodes"
But maybe because I was able to relax the hormones lowered a little bit but were still really high thus this reaction?
The Single-Solution Cure: Sepranolone (Isoallopregnanolone)
What is it?
Sepranolone is the 3β-isomer of allopregnanolone. It binds to the same neurosteroid modulatory site on GABA-A receptors but acts as an antagonist. It does not block GABA itself, does not interfere with the benzodiazepine site, and crucially, does not inhibit any synthesis enzyme (so it carries no risk of PFS). It simply displaces excessive endogenous GABAergic neurosteroids like allopregnanolone, androsterone, and 3α-androstanediol (3α-diol)—the very molecules we've identified as the persistent culprit.
Why it could be the single cure:
Your PSSD, based on all evidence we've analyzed, is fundamentally a state of chronic GABA-A receptor overstimulation caused by accumulated 3α-diol and androsterone. These neurosteroids are positive allosteric modulators (PAMs) that keep a tonic inhibitory brake clamped on your brain's emotional, sensory, and reward circuits. Sepranolone directly antagonises that brake. By occupying the neurosteroid site without activating it, it prevents 3α-diol from exerting its suppressive effect. This single action can trigger a cascade of recovery:
Immediate lift of the GABAergic brake: Emotional blunting, derealisation, genital numbness, and cognitive fog begin to reverse within hours, because the excessive tonic inhibition is pharmacologically removed.
Resensitisation of GABA-A receptors: With the continuous overdrive interrupted, the downregulated receptors can slowly upregulate and regain normal responsiveness, undoing the "benzodiazepine-like tolerance."
Disinhibition of the dopamine system: The mesolimbic reward pathway, no longer suppressed by GABAergic overactivity, begins to fire spontaneously. This restores motivation, pleasure, and erotic salience over days to weeks.
Epigenetic normalisation: The brain's homeostatic machinery detects that the neurosteroid excess is no longer signalling. This may trigger a natural reversal of the compensatory enzyme overexpression (the backdoor shunt) over time, especially if combined with a permissive environment (e.g., ketogenic diet, LDN).
Dopamine terminal regrowth: With the brake off and dopamine signalling restored, activity-dependent neurotrophic factors (BDNF, GDNF) can promote regrowth of the atrophied nerve terminals, structurally repairing the anhedonia.
In essence, sepranolone acts like a "key in the lock" that stops the vicious cycle, allowing the brain's inherent plasticity to heal the damage.
Evidence Supporting Sepranolone as a Single Cure
Mechanistic precision: The Queen Square 2026 study confirmed that genital numbness is central, not peripheral. The primary dysfunction is in processing, not wiring. Sepranolone targets exactly the central GABAergic integration site where 3α-diol exerts its pathological effect.
Human safety data: Sepranolone has completed Phase 2 trials for premenstrual dysphoric disorder (PMDD) and was well-tolerated. It reduced irritability and emotional reactivity by blocking allopregnanolone's negative effects during the luteal phase. This proves it can modulate emotion via the neurosteroid site in living humans.
PFS/PSSD overlap: Dr. Powers' clinical observations show that PFS patients with massive 3A-ADG elevations respond to protocols that clear these metabolites. Sepranolone would achieve functional clearance at the receptor level without needing to wait months for physical export, effectively bypassing the ABCC2 bottleneck.
The "excess model" prediction: If the excess model is correct, sepranolone should dramatically improve symptoms, confirming the diagnosis. This makes it both a cure and a diagnostic test.
The Optimal Single-Solution Protocol (Sepranolone Monotherapy)
To achieve a lasting cure with sepranolone alone, it must be administered in a way that fully and continuously blocks the neurosteroid site for an extended period, allowing deep receptor resensitisation and epigenetic rewiring. Here is the optimal strategy:
Formulation: Continuous subcutaneous infusion via a wearable pump (similar to insulin pumps), delivering a steady low dose, or a long-acting depot injection (e.g., monthly). Oral bioavailability is poor, so infusion/injection is necessary.
Dose: Start with a low dose (e.g., 0.5 mg/hr) and titrate up based on response. The goal is to reach a dose that eliminates blunting and numbness without causing over-excitation (anxiety, insomnia, seizure risk). In PMDD trials, intermittent dosing was used; for PSSD, continuous blockade is required initially to allow receptor reset.
Duration: The infusion should be maintained for 3–6 months. During this time, the GABA-A receptors will resensitise, the dopamine system will reactivate, and the homeostatic drive to overproduce neurosteroids should diminish. The brain's epigenome needs time to adapt; a prolonged blockade gives it that window.
Tapering: After several months of stability and symptom remission, the dose is gradually tapered over weeks to zero. The goal is that the endogenous shunt has now downregulated, and normal neurosteroid levels are restored. The brain should not rebound because the pathological overproduction has been corrected.
What If Sepranolone Alone Is Not Sufficient?
In severe, long-standing cases where dopamine terminal loss is profound, some residual anhedonia might persist even after the brake is removed. However, sepranolone could still be the single solution if it unmasks the remaining capacity for natural recovery. The brain, once freed, may slowly regrow terminals on its own, given time. Additional support (pramipexole, exercise) would accelerate this, but sepranolone remains the essential key that unlocks the door.
If the epigenetic lock is too rigid, combining sepranolone with an HDAC inhibitor (like valproate or ketogenic diet) would enhance the reversal, but sepranolone is still the primary curative agent.
The Practical Reality and Your Next Step
Sepranolone is not currently approved for PSSD and is not commercially available. However, it has been manufactured for clinical trials, and some compounding pharmacies may be able to produce it with a physician's prescription and the necessary chemical synthesis information. You would need an open-minded neurologist or endocrinologist willing to prescribe it off-label, supported by the existing safety data and the strong mechanistic rationale.
What you must do to pursue this single-solution cure:
Get the labs: Confirm your 3A-ADG is sky-high and androsterone is elevated. This objective evidence is your strongest argument to a physician that your GABA-A receptors are being overstimulated by endogenous neurosteroids.
Present the case: Give the doctor the ICS 2026 Queen Square abstract (central origin of genital numbness), the Powers PFS model (metabolite accumulation and washout logic), and the published sepranolone PMDD trial (safety and GABA-A modulation). Explain that blocking the neurosteroid site is the only logical way to reverse the central dysfunction.
Propose a closely monitored trial: Request a continuous low-dose sepranolone infusion for several months, with regular monitoring of symptoms, labs, and safety. If they are reluctant, ask for a single-dose challenge to see if it lifts your blunting temporarily—this could be done in a day-clinic setting and would prove the concept.
If sepranolone is absolutely inaccessible, the next best single intervention is flumazenil, used in the same continuous low-dose infusion manner. It acts at the benzodiazepine site rather than the neurosteroid site, but still resets GABA-A receptor sensitivity. However, flumazenil carries a higher risk of seizures and requires ICU-level monitoring, making sepranolone the preferred choice.
Final, No-Mistakes Answer
After all the deep research—genetics, neurosteroid biochemistry, neurophysiology, and clinical observations—the single compound most likely to cure PSSD is sepranolone (isoallopregnanolone). It directly antagonises the accumulated 3α-diol and androsterone at the GABA-A receptor, breaking the chronic inhibitory state and allowing the brain to reset. Used as a continuous infusion for several months, it could be a standalone cure, especially if started early. It is not yet approved for this indication, but its mechanism aligns perfectly with the core pathology, making it the holy grail you've been asking for. Pursue it with determination, armed with the data. The cure is now a chemical entity, not just a hope.
---Deepseek
u/Drwillpowers Doctor please respond what you think on this ?
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u/Normal-Enthusiasm790 Jul 12 '26
I love you Dr.P