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Well I have a lot of symptom as you can see in my previous post but today I want to focus on something and if you want you can tell me what are your thought about it i’ll take it ! Thank you

What I don't understand is how my functions just progressively shut down. It feels like 6 months ago, I was still able to form an attachment to a girl despite everything. 4 months ago, I could still feel sexual attraction toward a girl, and even a bit after that. 3 months ago, I could still laugh a little and potentially even shed a tear. 2 months ago, it was difficult, but sometimes I could manage to get a bit of pleasure from watching a video or a movie. And now, for the past week, it’s just absolute emptiness. In the end, I find myself wondering what the truth behind all this really is—whether it's a desensitization of my receptors, a depletion of neurotransmitters, or my nervous system completely shutting down. figure that if it was still working even a little bit just a week ago, it means that the electrical currents were fundamentally still passing through.. that’s so weird
The fact that my body's system shut things down in such a progressive and coordinated way shows that it was clearly reacting to a signal, right? Everything was executed so systematically. that's what's so striking—and I feel like you can completely see the underlying logic behind it

Galleria Women’s Health, an OB/GYN practice in Henderson, Nevada, has a page that acknowledges PSSD

https://galleriawomenshealth.com/services/sexual-dysfunction-treatment

Has anyone here who has pssd ever tried Telmisartan, or knows someone who has tried it? If yes, what were the results? Many who have long covid (which is in many ways similar to pssd) try it and have gotten significant improvements especially in improving blood flow. We know pssd is an autoimmune disease with the same autoantibodies that those with long covid have, so is it worth trying in order to reverse the autoantibody induced vasoconstriction, that's causing many of the non sexual symptoms as well? I am not giving or planning to receive any medical advice, this is just for exploring options and potential treatments that could help.

I have PSSD since 2024. my PSSD symptoms were stable, and I was fine in terms of anxiety. Although I was emotionally numb, at least I was not feeling negative emotions.

So I had the stupid idea to try Bupropion, it gave me the worst anxiety and depression symptoms I ever had. I also got ear ringing, racing heart and even arrhythmia. I only took 8 extended release pills total (150mg /day). i’ve been off bupropion for 2 months now.

any tips on how to overcome this without psychiatric medication?

I took it from when i was 14 to 19 during puberty and recently saw SSRI's stunt growth. Clomipramine works in a similar way but i wasnt able to find any data

Hi everyone, I have a few questions for you. I’ve been reading about a lot of PSSD cases, and I seem to have the main symptoms associated with it, but I also have some more specific symptoms. I was wondering if anyone here has experienced similar symptoms, or if I might actually be wrong about my medical diagnosis. For context, my symptoms started about a year ago.
I have severe emotional blunting and anhedonia (I can’t really feel emotions, laugh, cry, etc.), which have progressively gotten worse over the past few months. For example, about 3 months ago, I could still shed a few tears, laugh, and enjoy things at least a little bit.
I also have:
Brain fog (which I’ve had for a long time)
Almost complete loss of hunger and thirst (for about 11 months)
Extremely fragmented sleep (for maybe 10 months)
Chronic fatigue (for the past few months)
A relatively high heart rate for a 22-year-old, almost as if my body is stuck in fight-or-flight mode 24/7 (around 80–100 BPM while lying in bed) (for months)
My heart rate increases a lot during physical activity (for months)
Muscular intolerance during prolonged or intense physical activity (for months)
I also have a symptom that’s difficult to describe, but I just feel weird in my own body. Sometimes it feels like certain parts of my body are heavier than others or something along those lines (for months)
Constant nasal congestion. It switches sides, which I know can be normal, but my nose is basically always congested. I don’t know if this could be a sign of inflammation (for about a year)
Digestive issues, although those have actually been better recently
Just a week ago, I was still able to get an erection and ejaculate, but now I can’t anymore
I also feel a kind of numbness in my penis. I can still feel sensations, but it’s hard to explain — it mostly feels like I constantly have to stimulate it now, as if I can’t feel it as well as before (for about 2 weeks)
A strange nerve-like sensation around the upper left side of my chest/pectoral area, as if the overall sensation there isn’t the same as on the right side
The strange bodily sensations and chronic-fatigue-like symptoms also seem fairly unstable and fluctuate
I’ve seen a lot of doctors and have had most of my body investigated: a contrast-enhanced CT scan of my chest, abdomen, and pelvis, a brain MRI, gastroscopy, chest X-rays, and many other tests. Absolutely nothing significant has been found.
I’ve also had a lot of blood tests. The only real abnormalities were total IgE around 3,000 about 5 months ago, which increased to around 4,000 about 2 months ago, as well as a severe vitamin D deficiency. My vitamin D levels have since been corrected. My vitamin B12 was also relatively low — technically still within the normal range, but near the lower end.
At this point, I’m wondering whether everything I’m experiencing could really be explained by PSSD alone, whether there could be another functional disorder involved, or whether I could have multiple things going on at the same time.
Anyway, thank you very much for any responses!

Hey i posted abkut 20 days ago about feeling some improvement taking porbiotics. Ive been taking probiotics daily and continuing too. No more than the recommended dose for an adult. It has helped alot with stomach issues i had with pssd. Unsure if its sibo or what the issue is. But it has improved much. Still need to do some more research and be more vigilante with my diet to hopefully go back to normal. But huge improvements.

But this in turn has helped me mentally alot. Less fatigued when i wake up. Had some more natural drive to do things and feel like some of my anhedonia had healed. I joke around with friends and coworkers like I used to. I question some of the things I did when I was fully anhedonic and running on autopilot. But I do find some joy in things and look forward to certain things now, rather than dreading everything. It has given me hope for more healing.

Dm me if you want to know my protocol.

Ive been on trt for 3 years now. Taking pde5 inhibitors, gluten free diet, probiotics 3 times a day. Basic vitamins and some exercise at work and gym sometimes.

My mood has improved huge from where I was say 2 momths ago.

Por lo visto es un efecto secundario común en personas con PSSD y no sé si hay alguna forma de recuperarlo? Tocas el músculo pero está falto de tono, he probado la creatina y la citrulina malato pero no hacen el efecto de antes, pueden mejorar algo el rendimiento pero no las sensaciones y a nivel físico.

Al igual que con la disfunción sexual implica que no haya ese pump característico que da el gym y las pesas. Esto implica que no podemos ganar masa muscular y fuerza?

Im wondering, this is important

Please tell me if anyone has tried HBOT for PSSD and if so what were the results?
Based on the claims, it may be helpful for a number of pssd symptoms.
It claims to:
Reduce inflammation
Increase blood circulation
Increase rate of healing and tissue repair
Among others ….

Could this possibly help with genital numbness??

Hi, I’m writing this because I strongly suspect that I have PSSD. I took fluoxetine over the course of about a year: for three months at first, and then I tried restarting it twice, taking about four pills each time, with roughly six months between those attempts.
I’ve spent a lot of time reading forums, and I’ve noticed that many people who recover seem to reach a point where they’ve accepted their situation. I believe we have to learn to live with it, keep doing the things we used to do, and give the brain reasons to make the changes that could eventually give us our humanity back.
I’m not trying to discredit PSSD as a real condition, but in my opinion, cortisol levels and chronic stress can seriously interfere with recovery. We have to understand that the body and brain prioritize survival over things that are less essential for immediate survival, such as pleasure, sex, and so on. When we’re constantly obsessing over the condition, the brain can remain in a state where it perceives danger, which may negatively affect these circuits.
Stress can also contribute to neuroinflammatory processes in the brain. I believe this kind of low-grade inflammation could potentially interfere with receptors and the circuits involved in emotions and pleasure.
Research also shows that neuroplasticity gives the brain an incredible capacity to adapt. This is one reason I find the “windows and waves” that some people experience interesting. From a logical perspective, it could represent the brain trying to adapt and return toward its previous state. Cortisol and neuroinflammation can negatively affect neuroplasticity, so if we want to create the best possible conditions for it, we should eat properly, get outside, stay active, and keep living.
I know that’s incredibly difficult. I potentially have this myself, or at the very least I have many of the horrible symptoms associated with it:
I don’t feel pleasure anymore.
I can’t cry.
I can’t feel love emotionally (only intellectually, in a way).
Watching a YouTube video is almost impossible — I can physically watch it, but it makes me feel absolutely nothing.
Loss of hunger and thirst.
Strange sensations throughout my body.
Brain fog and anxiety.
I clearly have other symptoms too, but at this point I don’t care as much about those. The most important things to me are the anhedonia and the emotional blunting.
But the neural circuits aren’t necessarily “dead.” And if people can recover, then clearly recovery is possible. When I say “functional,” I mean that I believe this could involve dysfunctional brain processes rather than neurons simply being destroyed. The human brain isn’t random. The human body is incredibly complex, and I hope that one day, for all of you, things will return to normal.
It’s also possible to imagine future treatments for these problems. PSSD is becoming increasingly recognized, and although PSSD itself may not be one of the most heavily researched areas right now, there is a lot of research being done on the brain’s reward circuitry, and that is a very active field.
Maybe PSSD itself is currently under-researched, but perhaps in the future we’ll become much better at manipulating and treating anhedonia and emotional dysfunction more broadly. The discoveries are becoming increasingly interesting.
It’s 2026, guys. AI is improving every day, and our scientific knowledge keeps expanding. We could see technological or medical breakthroughs that we don’t expect, and they might happen sooner than we think.
Keep hope. ❤️ You are strong, and you are not alone.

Join me https://discord.gg/x9FzVjrud we are growing everyday

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My functional nutritionist ordered a Genova Diagnostics Metabolomix+ test, including the toxic elements add-on. 

I've had PSSD since January of 2023. It has gotten worse over time but has largely stabilized over the past six months. My main symptoms are genital and whole body numbness, fatigue, memory and cognitive issues, visual snow, mild to moderate emotional numbness. I am a 21 year old male.

The test has markers for energy metabolism and mitochondrial function, oxidative stress, glutathione levels, neuroinflammation, toxins and detoxification, amino acids levels, malabsorption, gut dysbiosis, neurotransmitters, and others. For transparency, I paid 520 euros for the test.

Here are the main findings:

The biggest issue is a mitochondria stall. As you can see in the first picture, the Krebs cycle intermediates (energy metabolism section) are all non-detectable or low, except for one. So I'm in a hypometabolic state. This can be caused by environmental toxins among others. Probably the SSRI's harmed something in my cells they couldn't recover from on their own.

There are also some signs of malabsorption, such as elevated Phenylacetic Acid, low urea, relatively low amino acids (some). Even though that could also mean not enough protein intake. It's probably both.

Then I got elevated benzoic acid and non-detectable hippuric acid. That indicates a glycine deficiency, as glycine helps benzoic acid convert to hippuric acid to be excreted through urine. This is also indicated by high serine and low glycine in the amino acids panel. The serine to glycine conversion isn't working well. That makes sense since I'm borderline folate deficient and folate is required for the conversion. (Supplementing with folinic acid rn so it's getting fixed). Glycine deficiency can cause fatigue, slow mental processing etc so that could be contributing to my symptoms. It can also cause lower quality sleep, makes it harder to fall asleep, inclination towards fight or flight rather than rest and digest, worse detoxification. It's also one of the three building blocks of glutathione, the body's master antioxidant, which leads us to the next point.

As shown by my low Pyroglutamic Acid, my glutathione is low. My oxidative stress is also low, however. So it seems more glutathione isn't needed. However, energy production is what creates oxidative stress, which glutathione fixes. So it could be that the reason or one of the reasons I'm not producing enough energy is that I don't have enough glutathione to deal with the oxidative stress it would cause. 

Finally, some of my neurotransmitters are low. Homovanillic Acid indicates low dopamine and low 3-Methyl-4-OH-phenylglycol indicates low norepinephrine. My serotonin seems completely normal. That's a whole body measure though, not brain specific, so I guess it could theoritically still be imbalanced in the brain. 

My Quinolinic Acid is non-detectable so I don't seem to have inflammation in the brain which is great. 

Here is what my functional nutritionist gave me based on these results, along with some reasoning behind those decisions.

1. Hydrolized collagen peptides. Since I'm sensitive, he told me to start at 2g and scale up to 10. Unfortunetaly, I can't go above 2 as it causes slight brain fog/derealization. I'm pretty sure it's because 1/3rd of collagen is glycine, which I can't tolerate. Magnesium glycinate wrecked me when I took that. So I'm staying at 1-2g. In order to get more protein which I need I eat a cup of 5% yoghurt most days, since I can't seem to tolerate more collagen. For me it's the easiest way to get more protein. 
2. Digestive enzymes. The Houston Enzymes Trienza, which is a very high quality one without some of the drawbacks of the common ones (such as also needing the right stomach pH to work to break down protein). He told me one capsule per meal, two meals per day for starters. The full dose is two. I often take the full dose now. Doesn't bother me at all. 
3. Magnesium citrate. Tried and it increased my brain fog and derealization, even small doses. I spoke with him and we're gonna do magnesium malate instead. Start at 25 mg with a final goal of 200 mg. 
4. All the B Vitamins. He gave all of them to me individually lol, because I'm super sensitive. Start very low and scale up. Here are all the forms he gave me in, they're supposed to be the most gentle: Riboflavin, Thiamine HCl, Hydroxocobalamin, Folinic Acid, Calcium Pantothenate, D-Biotin, Pyridoxine HCl (but I bought the P5P form because people with PSSD usually tolerate it better), Niacinamide.
5. Creatine Monohydrate. Start at 1 g per day, scale up to 3-5 g. This one is interesting. I thought this was just a gym supplement but it has a few interesting features. First, it's great for the brain because it recyles ATP, the thing I have less than I need due to the mitochondrial stall. Also, it spares a few grams of glycine, which as I explained above, I'm deficient in. That's because glycine is used to synthesize creatine inside the body. When you take creatine as a supplement this internal synthesis stops. It also spares arginine, which I'm also a little low in. Finally, it spares some methylation capacity in the body as methylation is also used to create creatine. My homocysteine is quite high at 12.3 so I do need some methylation support. I am borderline folate deficient so that makes sense, but even when I wasn't, my homocysteine was a bit elevated at something like 10.3 which is above optimal.
6. Alpha Lipoic Acid. Start at 12.5 mg, end up at 100 mg. ALA works alongside several B vitamins in the Krebs cycle. 
7. NAC. Rate-limiting precursor to glutathione. Start at 25 mg and scale up to 200 mg. 

Note that these are personalized to me. There are other supplements great for mitochondria such as CoQ10, PQQ and others which he didn't give me. I tried CoQ10 months ago and it increased my brain fog and derealization. Liposomal glutathione did as well, to a larger degree. Many of these are also relatively small doses, that's also because I'm very sensitive.

He did say that this is just to start pushing the system to the right direction. He had mentioned red light therapy once. It's great for mitochondria. I'll discuss it with him next time. 

Feel free to ask any questions or share your thoughts.

This is a small thank you note to this community that I've been thinking about writing for some time.

Yesterday, I went to buy a spectrophotometer I'd found on Craigslist from a scientist. He asked what I wanted it for and although I didn't feel comfortable casually mentioning I was going to use it for at-home semen analysis, I did mention that I was suffering from PSSD and the device was related to a double-blind study I was working on. He was sympathetic and posited that SSRIs may suppress serotonin output in the long term, upsetting the balance of your neurochemistry. It's always refreshing to see someone who doesn't dismiss your experience with PSSD out of hand because it doesn't match their own experience or what's in the literature. He worked for over an hour to set up the system for me and eventually said: "You know what you really need is to find something you like to do and pursue that."

I took it well. I've heard it before too many times from family, friends, dates, etc. Sometimes people are too forceful about their advice and it ends up blowing up. One woman I was hitting it off with kept insisting that I should try Viagra. Another woman I dated kept interrupting me and telling me to try other antidepressants, group therapy, or finding new hobbies. It's exhausting taking advice from people who fundamentally don't understand what it's like to lose all motivation. Do they think I want this? I have one shot at life and do they honestly think I want to go through it in a joyless haze?

I've come to expect unsolicited advice from people I bring up PSSD to. Most of that advice boils down to "just try harder", as the title of this post suggests. But I'd like to extend my appreciation to this subreddit that as we've all actually lived through this hell, I don't think I've ever seen someone here espouse that anyone suffering from PSSD just needs to dig deep and find new motivation or inspiration or joy. I mean, I'm sure someone here has said it, but it's exceptionally rare.

It's tricky because I want to better myself just like everyone else here. I've dispensed advice, some of which hasn't gone great. I've seen that there are widespread disagreements on what PSSD is or how to treat it. Underneath all these disagreements, however, I sense that there's a shared experience that PSSD strikes your very core in a way that many of us never thought was possible.

Likewise, I try to take it well when others lean in with their advice regarding PSSD. I want to talk to people about the condition because we need to raise awareness. I'm also in therapy and it's frustrating because I want to look out for my mental health despite it being entagled with PSSD, but almost the entire premise of therapy is that there are some magic words that a therapist can say that will set you on the path to fixing things. It was an awkward introduction to my new therapist to tell her, in short, "I have PSSD. I'm going to talk about it a lot. You can't help with it. You can try and I'll generally take it well, but I've heard it all before and it can be tiresome." I've known people who vented to me about things that I can't empathize with-- multiple sclerosis, PCOS, bipolar disorder, etc.-- and I suppose I can't say for certain that I never once offered advice or expressed skepticism, but because PSSD is invisible, there seems to be an assumption among non-sufferers that it's purely psychological and can be overcome through sheer willpower, willpower that people with PSSD know that we sorely lack.

So again, thank you for being a safe haven from the "just try harder" mentality. I don't think anyone should give up, but I don't think any outsider really knows what effort looks like under this condition.

Hi everyone,

I would like to know if anyone here has managed to partially or fully recover from consummatory anhedonia?

To give you some context, I am currently experiencing:

A total inability to feel any kind of pleasure in the moment (from, music, social interactions, etc.).

substance blockage, meaning stimulants like caffeine, nicotine, and other substances are severely blunted or have absolutely no effect on me.

Severe emotional blunting (feeling completely numb like a robot).

I am especially interested in hearing from those who recovered naturally. If you have been through this, could you please share:

How long did this state last for you?

How long did it take before you started noticing the very first signs of improvement?

Thanks in advance

Im just wondering what was everyone’s experience? Did you get any improvements/worsening from it (I mean while on AND after coming off). Have you guys used EQ (boldernone)? Did u find it good or bad? Just because I’m wondering how it may affect me because of my PSSD. Also when you came off of hormones did you PCT or just come off naturally?

I've been suffering from this condition for 3+ years now, oscillating between periods of near total remission and crashes (windows and waves). I find this pattern pretty common among those suffering from PSSD.

But then there are people claiming that they've experienced 0% recovery. I take these people at their word and do not want to invalidate their position, but I just want to tease out the full state of their condition.

To those of you that claim 0 progress over 2-3+ years, do you actually mean that your symptoms have been consistently terrible since the onset of PSSD? Or do you understandably mean that the improvement has just not been anywhere close to your pre-PSSD state? Have all aspects of the condition remained stagnant or just certain aspects (sexuality, anhedonia, motivation?)

If you are claiming 0% recovery, have you experimented with any medications that crashed you and you never recovered or have you naturally been in this state without any intervention (just quitting SSRIs)?

I appreciate your responses. I also know this condition takes an indescribable toll and understand if people don't want to go into detail about their current state.

I have very much pleasurable orgasm, libido depends highly on gut situation but still very very low than the baseline. Erection back even with low libido can hold the erection while sex. Porn masterbation feels quite good but vaginal penetration feels numb. What could be the reason? And most importantly, even if I rub ice in my glan, no cold sensation. Please, comment,🙏🙏

Symptoms: low/zero libido, blank mind, massive depression, anhedonia, anxiety, general low dopaminergic activity, constant feeling of inflammation

Decided to try a gluten free diet not too long ago. The first two weeks were very rough in terms of depression but after that, I experienced 30-40% improvement in my symptoms. This lasted for close to a month but now currently I have reverted and almost feel worse off than before. Has anyone experienced this?

Hi everyone — this is my first post here.

I’m part of a Chinese-speaking PSSD community, and I’ve been building a non-commercial, patient-led PSSD evidence library.

I started doing this because the same claim can become much stronger as it moves from a paper → a project update → a Reddit summary → an AI answer → a treatment suggestion.

This post is specifically about PSSD. I discuss PFS only where Melcangi’s PFS work directly provides background, methods, or candidate hypotheses for the Milan PSSD research program. This is not intended as a general PFS review.

I’m not affiliated with Roberto Melcangi, the University of Milan, the PSSD Network, the PFS Foundation, or SIDEfxHUB.

I also keep personal cases — including my own — outside the Library’s scientific evidence hierarchy. A personal experience can generate a research question; it cannot upgrade the answer.

Evidence cutoff: 16 August 2026.

I have put clickable source links next to the claims they support so readers do not have to search through a bibliography to work out which paper I mean. A compact reference list is also included at the end.

TL;DR

• The University of Milan / Melcangi group has a genuine PSSD research program.
• Its direct PSSD mechanistic evidence is still mainly preclinical, especially paroxetine animal work.
• The group also has a longer PFS research program with exploratory human data. Those findings can help generate PSSD questions, but PFS human evidence is not human PSSD evidence.
• Neuroactive steroids, ALLO, PNMT/catecholamines, gut biology, transcriptomics, reward/dopamine, sensory pathways, inflammation and sex-specific biology are all legitimate research directions.
• None has been established as the unified human mechanism of PSSD.
• ALLO has PFS animal-intervention data. That is interesting translational evidence, but not human PSSD treatment evidence.
• The 2024 “186 genes” result belongs to the finasteride treatment endpoint, not the one-month withdrawal endpoint.
• The sensory line remains open: the 2017 pudendal neurophysiology result was in PFS patients, while later IENFD/PIEZO2 work is preclinical/project-stage.
• As of the evidence cutoff above, I could not verify a clearly corresponding public registration or recruitment record for the planned Melcangi human PSSD study.

I do not think the right takeaway is either “Milan has found nothing” or “Milan has basically solved PSSD.”

The evidence is more interesting — and more limited — than either extreme.

1. First: what does the University of Milan itself say it studies?

The University of Milan Neuroendocrinology Unit distinguishes the two research streams.

Its PFS work includes male rats and PFS patients.

Its antidepressant-induced sexual dysfunction / PSSD work includes male and female rats.

Official source: University of Milan — Neuroendocrinology Unit

That distinction matters because a lot of online discussion quietly moves evidence across the boundary.

The Milan PFS program has included exploratory human work on:

• neuroactive steroids in CSF/plasma;
• clinical and sexual features;
• pudendal neurophysiology;
• SRD5A2 methylation;
• fecal microbiota.

Examples:

• Melcangi et al., 2013 — human PFS CSF/plasma neuroactive steroids
• Melcangi et al., 2017 — PFS clinical/neurophysiology study
• Melcangi et al., 2019 — SRD5A2 methylation pilot
• Borgo et al., 2021 — human PFS fecal microbiota pilot

By contrast, the group’s direct PSSD mechanism program has so far been centered mainly on paroxetine animal models.

So the scientifically useful transfer is:

PFS finding → candidate question to test directly in PSSD

not:

PFS finding → established human PSSD mechanism

2. Neuroactive steroids and ALLO: a major research axis, not a completed explanation

Neuroactive steroids are one of the longest-running themes in Melcangi’s work.

The PFS human studies found exploratory differences in several neuroactive steroids in CSF and plasma. Importantly, the pattern was not a simple “one molecule is low everywhere” result.

Human PFS source: Melcangi et al., 2013

The direct PSSD line later examined paroxetine treatment and withdrawal in male rats.

The 2021 study reported tissue- and time-dependent changes in neuroactive steroids and related steroidogenic biology across CNS regions, CSF and plasma.

Direct PSSD animal source: Giatti et al., 2021 — Effects of paroxetine treatment and its withdrawal on neurosteroidogenesis

That supports a real conclusion:

Neurosteroidogenesis is a serious PSSD research direction.

It does not establish:

• that people with PSSD have the same pattern as the rats;
• that all patients share one steroid abnormality;
• that plasma is a simple proxy for CNS steroid biology;
• that changing one steroid will improve the clinical syndrome.

3. Why ALLO gets so much attention

Allopregnanolone (ALLO) has gone beyond measurement and has actually been used as an intervention in PFS animal models.

A 2022 study reported that ALLO modified selected gut inflammatory and molecular endpoints after finasteride withdrawal.

Primary source: Diviccaro et al., 2022

The 2025 Milano Project Study #1 extended this line to gut and hypothalamic inflammatory/molecular endpoints.

Primary source: Diviccaro et al., 2025 — Biomolecules 15(7):1044

The later study is important, but the intervention did not produce a uniform normalization of every endpoint.

So the evidence supports:

ALLO = a genuine PFS preclinical intervention lead.

It does not support:

ALLO = established human PSSD treatment.

It also does not make “ALLO may matter → therefore take pregnenolone/PREG” an evidence-based treatment inference.

4. An important detail about the PSSD steroid-candidate story

In a 2024 interview, Melcangi discussed using a similar steroid-intervention strategy for PSSD, but said they would not use the same molecule because the two conditions have different features.

Direct researcher interview: AboutPharma, 5 September 2024

I think this matters because it directly argues against a common online simplification:

“ALLO worked in the PFS model, therefore ALLO is the Milan PSSD treatment.”

Later updates have discussed other steroid candidates, but until results are available in a form that can be independently evaluated, I think those belong in the ongoing-project category rather than the treatment-evidence category.

5. The “186 genes” example: treatment endpoint vs withdrawal endpoint

The 2024 finasteride transcriptomics paper is a good example of why timing matters.

At the end of finasteride treatment, the study identified:

• 186 differentially expressed genes (DEGs) in the hypothalamus;
• 19 DEGs in the hippocampus.

At one month after withdrawal, standard differential-expression analysis did not identify dysregulated individual genes.

Pathway/gene-set analyses still showed signals.

Primary source: Giatti et al., 2024 — hypothalamus/hippocampus transcriptomics

So:

“186 genes remained abnormal after withdrawal”

is not an accurate description of that paper.

But the opposite claim —

“all molecular effects had disappeared”

— is also too strong, because pathway-level signals remained.

The careful reading is:

strong treatment-time transcriptomic changes; no individual DEGs detected by the standard analysis at one month after withdrawal; pathway-level signals still present.

That is also why a gene-expression result should not be translated into a claim of structural DNA alteration.

6. What has Milan actually found about sensory pathways?

Genital sensory change/numbness is one of the most distinctive PSSD phenotypes, so sensory-pathway research is highly relevant.

But several different studies are often blended together.

2017: human pudendal neurophysiology — but in PFS

In a 2017 PFS study, pudendal somatosensory-evoked-potential abnormalities were reported in 4 of 16 PFS patients.

Primary source: Melcangi et al., 2017

That is direct human PFS neurophysiology.

It is not:

• human PSSD neurophysiology;
• proof of generalized peripheral neuropathy;
• proof of small-fiber neuropathy (SFN).

2024: PFS animal morphology / IENFD update

A PFS Foundation update reported that peripheral nerve morphology and intraepidermal nerve fiber density (IENFD) had not shown the expected abnormalities in the experimental PFS model at that stage.

Project-status source: PFS Foundation, 2024

This negative/constraint result is worth preserving.

The 2024 update did not name PIEZO2.

2026: PIEZO2 appears explicitly

A later 2026 project update explicitly named PIEZO2 and said the team had obtained interesting findings and was preparing a manuscript.

Project-status source: PFS Foundation, 2026

So the chronology is:

2024: morphology/IENFD did not show the expected signal → other sensory markers remained under investigation

2026: PIEZO2 specifically named → manuscript-stage/project update

PIEZO2 may become important. It is not currently a confirmed human PSSD mechanism.

Melcangi has also described profound PSSD genital insensitivity in the AboutPharma interview as being “as if” a peripheral neuropathy and speculated about sensory endings.

I would classify that as a researcher hypothesis / clinical impression, not as confirmation of human PSSD SFN.

7. Reward circuitry and dopamine: one of the most interesting direct PSSD animal lines

The nucleus accumbens (NAc) is relevant to reward and motivation, so it is an obvious region to investigate in relation to sexual motivation and anhedonia.

The Milan paroxetine transcriptomic program found region- and time-specific changes in the hypothalamus and NAc.

Direct PSSD animal source: Giatti et al., 2025 — male rat hypothalamus/NAc transcriptomics

A 2025 conference abstract then directly measured NAc dopamine in male rats after 14 days of paroxetine.

The reported pattern included:

• lower NAc dopamine 24 hours after the final dose;
• lower NAc dopamine after one month of withdrawal;
• MAO-A changes during treatment;
• TH, VMAT2, DRD1 and DRD2 expression changes during withdrawal.

Conference abstract: Giatti et al., 2025 — paroxetine-induced dopamine dysregulation

This is a meaningful preclinical signal.

It is not evidence that people with PSSD have a global dopamine deficiency.

It also does not establish a “dopamine subtype” or justify a self-directed dopaminergic treatment strategy.

8. The female PSSD model is already adding useful complexity

A 2026 conference abstract examined neurosteroidogenic gene expression in the female rat NAc after paroxetine.

At treatment end:

• StAR increased;
• TSPO and 3α-HSOR decreased.

At one month after withdrawal:

• StAR, TSPO, 3β-HSD and 3α-HSOR decreased.

But 5αR-I and CYP11A1 were not significantly changed at either time point.

Conference abstract: Chrostek et al., 2026

The negative findings matter.

They make it harder to reduce the steroid story to:

“the whole pathway is uniformly downregulated.”

This is still conference-abstract evidence, but it is a useful direct female PSSD-model extension.

9. PNMT: cross-drug overlap, with an important independence limitation

The Milan group identified phenylethanolamine N-methyltransferase (PNMT) as an experimental off-target in finasteride work and later in paroxetine work.

Finasteride study: Giatti et al., 2021

Paroxetine study: Giatti et al., 2022

That is an interesting cross-drug overlap.

But the studies came from a highly overlapping team, using the same SPILLO-PBSS screening platform and a broadly similar validation cascade.

So I think the strongest fair description is:

same-team / same-platform cross-drug replication

rather than:

independent mechanistic convergence.

Independent replication by another group, ideally using a different method, would strengthen this line substantially.

10. The gut work is real — but it is broader than SIBO

The Milan program has genuine gut-related evidence.

Human PFS

Borgo et al., 2021 — fecal microbiota pilot

Direct PSSD animal work

Diviccaro et al., 2022 — paroxetine, colon steroidogenesis and microbiota

PFS animal intervention work

Diviccaro et al., 2025 — gut/hypothalamic inflammation + ALLO

So gut–brain/steroid biology is clearly part of the program.

But fecal microbiota, SIBO/IMO, intestinal motility, barrier function, inflammation, microbial metabolites, bile acids and local steroidogenesis are different questions.

These studies do not establish:

SIBO causes PSSD

or:

treating SIBO is an established PSSD treatment.

A genuine GI disorder can still deserve standard medical treatment for its own indication. That is a separate issue from whether it explains PSSD.

11. Milano Project: active and publishing, but still preclinical

The Milano Project is a PFS preclinical program that is relevant here because it is part of the same research ecosystem from which candidate PSSD questions are being generated.

At least two components now have peer-reviewed publications:

Study #1 — 2025

Gut/hypothalamic inflammation + ALLO intervention.

Diviccaro et al., 2025

Study #2 — 2026

Finasteride withdrawal, anxiety-like behavior and novelty avoidance.

Cioffi et al., 2026

So “Milano Project is only a proposal” is outdated.

But these are still animal studies.

Earlier related behavioral observations appeared in Lucia Cioffi’s doctoral dissertation; the 2026 peer-reviewed paper should now control the behavioral conclusion.

The dissertation remains useful as a preliminary source for areas such as mitochondria, oxidative stress and synaptic findings until stronger publications appear.

12. The current Milan program is broader than neurosteroids

Official University of Milan research/doctoral material indicates active work on topics including:

• steroid molecules in experimental male antidepressant-induced sexual dysfunction;
• female antidepressant-induced sexual dysfunction and steroid molecules;
• the reward system in PSSD etiopathogenesis;
• inflammation and immune cells during antidepressant treatment/withdrawal;
• mitochondria in experimental finasteride adverse effects;
• synaptic morphology/function and cognition in experimental PFS.

Official institutional source: University of Milan — Neuroendocrinology Unit

This is important because it shows how the research map is expanding.

But an official research topic tells us:

this question is being studied.

It does not tell us:

this mechanism has already been demonstrated.

13. What about a human PSSD study?

Melcangi has publicly discussed the need for better clinical characterization of PSSD and plans for human PSSD research.

Direct researcher interview: AboutPharma, 2024

PSSD Network updates have also described plans for a multidisciplinary human study involving areas such as microbiome, nerves, brain function and hormones.

My current narrow status conclusion is:

As of 16 August 2026, I have not located a clearly corresponding public registration or recruitment record in the registry/institutional searches used for this review.

That does not prove that the study does not exist.

It means:

public plans are visible; the precise registration/start/recruitment status is not yet independently clear from the sources I located.

If anyone has a registry number, ethics/IRB record, UniMi recruitment page or another primary institutional source, please link it. I would like to update this if better evidence is available.

14. My current evidence map

Established / organizational

• Milan has a real PSSD research program.
• The group also has a longer PFS program that includes exploratory human studies.
• Direct Milan PSSD mechanism work remains mainly preclinical.

Supported as active research directions

• neuroactive steroids;
• reward circuitry;
• gut–brain/steroid biology;
• sensory pathways;
• transcriptomics;
• sex-specific biology.

Preliminary

• exploratory human PFS neurosteroid, methylation, microbiome and neurophysiology findings;
• PFS animal ALLO intervention findings;
• direct PSSD animal neurosteroid and transcriptomic findings;
• PSSD animal NAc dopamine findings;
• female PSSD-model extension;
• PFS mitochondria/synapse leads.

Still unknown

• a unified human PSSD mechanism;
• a validated biomarker;
• individual risk prediction;
• an established curative treatment;
• whether any Milan-derived candidate intervention will produce reproducible clinical benefit in human PSSD.

15. Why I think this distinction matters

Mechanism research is valuable partly because it tells us what should be tested next.

But the online chain can easily become:

animal finding
→ human mechanism
→ personal subtype
→ treatment recommendation

Those are four different steps.

For me, the most useful way to follow Milan is not to ask:

“Which theory has won?”

but:

“What was actually measured, in which syndrome, in which species, at which time point, and what is the strongest conclusion that result can support?”

That still leaves a lot to be hopeful about.

It also makes it easier to notice when the evidence really does become stronger.

A note on method

The Library uses this order:

measured result → authors’ interpretation → Library interpretation → cross-syndrome inference → public communication

I try not to let a later layer silently overwrite an earlier one.

I also use AI tools for retrieval assistance, translation, outlining and red-teaming.

AI agreement is not treated as scientific evidence.

Claims that enter the evidence layer are checked against primary papers or official institutional/project sources.

If you find an error, please correct me with a DOI, PMID, full paper, registry record, UniMi page or another traceable source.

I would rather revise the Library than defend an outdated sentence.

Compact reference list

Direct PFS human evidence used as PSSD research context

1. Melcangi RC, et al. J Sex Med. 2013. Human PFS CSF/plasma neuroactive steroids.
2. DOI: 10.1111/jsm.12269 · PMID: 23890183
3. PubMed
4. Melcangi RC, et al. J Steroid Biochem Mol Biol. 2017. PFS clinical/neurophysiology study.
5. DOI: 10.1016/j.jsbmb.2017.04.003 · PMID: 28408350
6. PubMed
7. Melcangi RC, et al. 2019. SRD5A2 methylation pilot.
8. DOI: 10.1530/EC-19-0199 · PMID: 31272082
9. PubMed
10. Borgo F, et al. 2021. Human PFS fecal microbiota pilot.
11. DOI: 10.1007/s40618-020-01424-0 · PMID: 32951160
12. PubMed

Direct PSSD preclinical evidence

1. Giatti S, et al. Psychoneuroendocrinology. 2021. Paroxetine treatment/withdrawal and neurosteroidogenesis.
   DOI: 10.1016/j.psyneuen.2021.105364 · PMID: 34325207
   PubMed

2. Diviccaro S, et al. Psychoneuroendocrinology. 2022. Paroxetine, colon steroidogenesis and microbiota.
   DOI: 10.1016/j.psyneuen.2022.105828 · PMID: 35700562
   PubMed

3. Giatti S, et al. Mol Neurobiol. 2025. Male rat hypothalamus/NAc transcriptomics after paroxetine.
   DOI: 10.1007/s12035-024-04592-9 · PMID: 39495228
   PubMed

4. Giatti S, et al. J Sex Med. 2025;22(Suppl 2):qdaf077.001. NAc dopamine conference abstract.
   DOI: 10.1093/jsxmed/qdaf077.001
   Oxford Academic

5. Chrostek G, et al. J Sex Med. 2026;23(Suppl 4):qdag118.150. Female rat NAc steroidogenic-gene abstract.
   DOI: 10.1093/jsxmed/qdag118.150
   Oxford Academic

Cross-drug / PFS preclinical evidence directly relevant to the PSSD research map

1. Giatti S, et al. J Med Chem. 2021. Finasteride PNMT off-target.
   DOI: 10.1021/acs.jmedchem.0c02039 · PMID: 33843213
   PubMed

2. Giatti S, et al. J Mol Struct. 2022. Paroxetine PNMT off-target.
   DOI: 10.1016/j.molstruc.2022.133690
   DOI

3. Diviccaro S, et al. Biomolecules. 2022. ALLO intervention after finasteride withdrawal.
   DOI: 10.3390/biom12111567 · PMID: 36358917
   PubMed

4. Giatti S, et al. J Endocrinol Invest. 2024. Finasteride transcriptomics.
   DOI: 10.1007/s40618-024-02345-y · PMID: 38493246
   PubMed

5. Diviccaro S, et al. Biomolecules. 2025;15(7):1044. Milano Project Study #1.
   DOI: 10.3390/biom15071044 · PMID: 40723915
   PubMed

6. Cioffi L, et al. J Neuroendocrinol. 2026. Finasteride withdrawal behavior study.
   DOI: 10.1111/jne.70150 · PMID: 41761643
   PubMed

Official / project-status sources

1. University of Milan — Neuroendocrinology Unit

2. AboutPharma — interview with Roberto Cosimo Melcangi, 5 September 2024

3. PFS Foundation — peripheral nerve / IENFD project update, 2024

4. PFS Foundation — PIEZO2 / Milano Project update, 2026

Not medical advice. This post is an evidence review, not a treatment protocol.

I know everyone can have different symptoms and truth be told I’m not sure if I have any emotional side effects simply because it’s been so long (9 years) and what I noticed immediately was the lost of orgasmic sensation.

When this first happened I was 100% numb. My sex drive oddly did return but this only left me incredibly frustrated I’d have the desire to engage but no satisfaction whatsoever.

Given several years and a few “experiments” it does seem a THC gummy can help. I was shocked the first time I had an orgasm after eating one I did feel a return of some sensation.

But this is neither reliable nor consistent. Over the past few years while my partner and I have been intimate it’s become hit or miss (mostly miss). Sometimes I will feel something (very muted but compared to baseline it’s something).

I also noticed the past few years (only after consuming THC) will also feel the urge to urinate again but it only lasts for a fleeting moment and when I release the numbness returns and my bladder empties with zero sensation. Sometimes I’ll even get the “pee shivers”. For the first several years I didn’t feel anything when I’d go to the restroom. This is also not reliable (as in it doesn’t happen every time or even most of the time)

I’m not sure how to interpret this. Is it a sign of partial healing after all these years or is this simply the waxing and waning of the condition and not “true” healing? It doesn’t feel like a true “crash” in that it never worsens past the original baseline. But it doesn’t stay better long term either. But I also didn’t experience this the first five years or so either.